Substituted pyridinyl and pyrimidinyl derivatives as modulators of metabolism and the treatment of disorders related thereto

ABSTRACT

The present invention relates to certain substituted pyridinyl and pyrimidinyl derivatives of Fomula (Ia) that are modulators of metabolism.  
                 
Accordingly, compounds of the present invention are useful in the treatment of metabolic-related disorders and complications thereof, such as, diabetes and obesity.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Ser. No. 60/642,840, filedJan. 10, 2005, the disclosure of which is incorporated herein byreference in its entirety.

FIELD OF THE INVENTION

The present invention relates to certain substituted pyridinyl andpyrimidinyl derivatives that are modulators of glucose metabolism.Accordingly, compounds of the present invention are useful in thetreatment of metabolic-related disorders and complications thereof, suchas, diabetes and obesity.

BACKGROUND OF THE INVENTION

Diabetes mellitus is a serious disease afflicting over 100 millionpeople worldwide. In the United States, there are more than 12 milliondiabetics, with 600,000 new cases diagnosed each year.

Diabetes mellitus is a diagnostic term for a group of disorderscharacterized by abnormal glucose homeostasis resulting in elevatedblood sugar. There are many types of diabetes, but the two most commonare Type I (also referred to as insulin-dependent diabetes mellitus orIDDM) and Type II (also referred to as non-insulin-dependent diabetesmellitus or NIDDM).

The etiology of the different types of diabetes is not the same;however, everyone with diabetes has two things in common: overproductionof glucose by the liver and little or no ability to move glucose out ofthe blood into the cells where it becomes the body's primary fuel.

People who do not have diabetes rely on insulin, a hormone made in thepancreas, to move glucose from the blood into the cells of the body.However, people who have diabetes either don't produce insulin or can'tefficiently use the insulin they produce; therefore, they can't moveglucose into their cells. Glucose accumulates in the blood creating acondition called hyperglycemia, and over time, can cause serious healthproblems.

Diabetes is a syndrome with interrelated metabolic, vascular, andneuropathic components. The metabolic syndrome, generally characterizedby hyperglycemia, comprises alterations in carbohydrate, fat and proteinmetabolism caused by absent or markedly reduced insulin secretion and/orineffective insulin action. The vascular syndrome consists ofabnormalities in the blood vessels leading to cardiovascular, retinaland renal complications. Abnormalities in the peripheral and autonomicnervous systems are also part of the diabetic syndrome.

People with IDDM, which accounts for about 5% to 10% of those who havediabetes, don't produce insulin and therefore must inject insulin tokeep their blood glucose levels normal. IDDM is characterized by low orundetectable levels of endogenous insulin production caused bydestruction of the insulin-producing β cells of the pancreas, thecharacteristic that most readily distinguishes IDDM from NIDDM. IDDM,once termed juvenile-onset diabetes, strikes young and older adultsalike.

Approximately 90 to 95% of people with diabetes have Type II (or NIDDM).NIDDM subjects produce insulin, but the cells in their bodies areinsulin resistant: the cells don't respond properly to the hormone, soglucose accumulates in their blood. NIDDM is characterized by a relativedisparity between endogenous insulin production and insulinrequirements, leading to elevated blood glucose levels. In contrast toIDDM, there is always some endogenous insulin production in NIDDM; manyNIDDM patients have normal or even elevated blood insulin levels, whileother NIDDM patients have inadequate insulin production (Rotwein, R. etal. N. Engl. J. Med. 308, 65-71 (1983)). Most people diagnosed withNIDDM are age 30 or older, and half of all new cases are age 55 andolder. Compared with whites and Asians, NIDDM is more common amongNative Americans, African-Americans, Latinos, and Hispanics. Inaddition, the onset can be insidious or even clinically inapparent,making diagnosis difficult.

The primary pathogenic lesion on NIDDM has remained elusive. Many havesuggested that primary insulin resistance of the peripheral tissues isthe initial event. Genetic epidemiological studies have supported thisview. Similarly, insulin secretion abnormalities have been argued as theprimary defect in NIDDM. It is likely that both phenomena are importantcontributors to the disease process (Rimoin, D. L., et. al. Emery andRimoin's Principles and Practice of Medical Genetics 3^(rd) Ed.1:1401-1402 (1996)).

Many people with NIDDM have sedentery lifestyles and are obese; theyweigh approximately 20% more than the recommended weight for theirheight and build. Furthermore, obesity is characterized byhyperinsulinemia and insulin resistance, a feature shared with NIDDM,hypertension and atherosclerosis.

Obesity and diabetes are among the most common human health problems inindustrialized societies. In industrialized countries a third of thepopulation is at least 20% overweight. In the United States, thepercentage of obese people has increased from 25% at the end of the1970s, to 33% at the beginning the 1990s. Obesity is one of the mostimportant risk factors for NIDDM. Definitions of obesity differ, but ingeneral, a subject weighing at least 20% more than the recommendedweight for his/her height and build is considered obese. The risk ofdeveloping NIDDM is tripled in subjects 30% overweight, andthree-quarters with NIDDM are overweight.

Obesity, which is the result of an imbalance between caloric intake andenergy expenditure, is highly correlated with insulin resistance anddiabetes in experimental animals and human. However, the molecularmechanisms that are involved in obesity-diabetes syndromes are notclear. During early development of obesity, increase insulin secretionbalances insulin resistance and protects patients from hyperglycemia (LeStunff, et al. Diabetes 43, 696-702 (1989)). However, after severaldecades, β cell function deteriorates and non-insulin-dependent diabetesdevelops in about 20% of the obese population (Pederson, P. Diab. Metab.Rev. 5, 505-509 (1989)) and (Brancati, F. L., et al., Arch. Intern. Med.159, 957-963 (1999)). Given its high prevalence in modern societies,obesity has thus become the leading risk factor for NIDDM (Hill, J. O.,et al., Science 280, 1371-1374 (1998)). However, the factors whichpredispose a fraction of patients to alteration of insulin secretion inresponse to fat accumulation remain unknown.

Whether someone is classified as overweight or obese is generallydetermined on the basis of their body mass index (BMI) which iscalculated by dividing body weight (kg) by height squared (m²). Thus,the units of BMI are kg/m² and it is possible to calculate the BMI rangeassociated with minimum mortality in each decade of life. Overweight isdefined as a BMI in the range 25-30 kg/m², and obesity as a BMI greaterthan 30 kg/m² (see TABLE below). There are problems with this definitionin that it does not take into account the proportion of body mass thatis muscle in relation to fat (adipose tissue). To account for this,obesity can also be defined on the basis of body fat content: greaterthan 25% and 30% in males and females, respectively. CLASSIFICATION OFWEIGHT BY BODY MASS INDEX (BMI) BMI CLASSIFICATION <18.5 Underweight18.5-24.9 Normal 25.0-29.9 Overweight 30.0-34.9 Obesity (Class I)35.0-39.9 Obesity (Class II) >40   Extreme Obesity (Class III)

As the BMI increases there is an increased risk of death from a varietyof causes that is independent of other risk factors. The most commondiseases with obesity are cardiovascular disease (particularlyhypertension), diabetes (obesity aggravates the development ofdiabetes), gall bladder disease (particularly cancer) and diseases ofreproduction. Research has shown that even a modest reduction in bodyweight can correspond to a significant reduction in the risk ofdeveloping coronary heart disease.

Compounds marketed as anti-obesity agents include Orlistat (XENICAL™)and Sibutramine. Orlistat (a lipase inhibitor) inhibits fat absorptiondirectly and tends to produce a high incidence of unpleasant (thoughrelatively harmless) side-effects such as diarrhea. Sibutramine (a mixed5-HT/noradrenaline reuptake inhibitor) can increase blood pressure andheart rate in some patients. The serotonin releaser/reuptake inhibitorsfenfluramine (Pondimin™) and dexfenfluramine (Redux™) have been reportedto decrease food intake and body weight over a prolonged period (greaterthan 6 months). However, both products were withdrawn after reports ofpreliminary evidence of heart valve abnormalities associated with theiruse. Accordingly, there is a need for the development of a saferanti-obesity agent.

Obesity considerably increases the risk of developing cardiovasculardiseases as well. Coronary insufficiency, atheromatous disease, andcardiac insufficiency are at the forefront of the cardiovascularcomplication induced by obesity. It is estimated that if the entirepopulation had an ideal weight, the risk of coronary insufficiency woulddecrease by 25% and the risk of cardiac insufficiency and of cerebralvascular accidents by 35%. The incidence of coronary diseases is doubledin subjects less than 50 years of age who are 30% overweight. Thediabetes patient faces a 30% reduced lifespan. After age 45, people withdiabetes are about three times more likely than people without diabetesto have significant heart disease and up to five times more likely tohave a stroke. These findings emphasize the inter-relations betweenrisks factors for NIDDM and coronary heart disease and the potentialvalue of an integrated approach to the prevention of these conditionsbased on the prevention of these conditions based on the prevention ofobesity (Perry, I. J., et al., BMJ 310, 560-564 (1995)).

Diabetes has also been implicated in the development of kidney disease,eye diseases and nervous-system problems. Kidney disease, also callednephropathy, occurs when the kidney's “filter mechanism” is damaged andprotein leaks into urine in excessive amounts and eventually the kidneyfails. Diabetes is also a leading cause of damage to the retina at theback of the eye and increases risk of cataracts and glaucoma. Finally,diabetes is associated with nerve damage, especially in the legs andfeet, which interferes with the ability to sense pain and contributes toserious infections. Taken together, diabetes complications are one ofthe nation's leading causes of death.

SUMMARY OF THE INVENTION

The present invention is drawn to compounds which bind to and modulatethe activity of a GPCR, referred to herein as RUP3, and uses thereof.The term RUP3 as used herein includes the human sequences found inGeneBank accession number AY288416, naturally-occurring allelicvariants, mammalian orthologs, and recombinant mutants thereof. Apreferred human RUP3 for use in screening and testing of the compoundsof the invention is provided in the nucleotide sequence of Seq. ID. No:1 and the corresponding amino acid sequence in Seq. ID. No:2.

One aspect of the present invention encompasses certain substitutedpyridinyl and pyrimidinyl derivatives as shown in Formula (Ia):

or a pharmaceutically acceptable salt, solvate or hydrate thereof;

wherein:

X is N or CR₈ wherein R₈ is H or halogen;

Y is NH or O;

Z is CH or N;

R₁ is carbo-C₁₋₆-alkoxy, oxadiazolyl or pyrimidinyl wherein saidcarbo-C₁₋₆-alkoxy, oxadiazolyl and pyrimidinyl are each optionallysubstituted with 1 or 2 substituents selected independently from thegroup consisting of C₁₋₄ alkyl, C₁₋₄ alkoxy and C₃₋₅ cycloalkyl;

R₂ is H or C₁₋₄alkyl;

R₃ is C₁₋₄ alkoxy, O—C₂₋₄-alkynyl or hydroxyl;

R₄ is selected from the group consisting of H, C₁₋₄ alkoxy, C₁₋₄ alkyl,C₂₋₄ alkynyl and halogen;

R₅ is selected from the group consisting of C₁₋₄ acylsulfonamide, C₁₋₄alkoxy, C₁₋₄ alkyl, C₁₋₄ alkylamino, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio,cyano, heterocyclyl, di-C₁₋₄-dialkylamino and sulfonamide, wherein saidC₁₋₄ alkoxy, C₁₋₄ alkyl, C₁₋₄ alkylamino, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, di-C₁₋₄-dialkylamino and heterocyclyl are each optionallysubstituted with 1 or 2 substituents selected independently from thegroup consisting of C₂₋₄ alkynyl, C₁₋₄ alkoxy, C₁₋₄ alkylcarboxamide,C₁₋₄ alkylsulfonyl, C₃₋₅ cycloalkyl, C₃₋₅ cycloalkyloxy,di-C₁₋₄-alkylcarboxamide, hydroxyl and phosphonooxy, wherein said C₁₋₄alkylcarboxamide is optionally substituted with hydroxyl; or

R₅ is a group of Formula (A):

wherein “m”, “n” and “q” are each independently 0, 1, 2 or 3; “r” is 0,1 or 2; and “t” is 0 or 1;

R₆ is H or halogen; and

R₇ is H or C₁₋₄ alkyl.

One aspect of the present invention pertains to pharmaceuticalcompositions comprising at least one compound of the present inventionand a pharmaceutically acceptable carrier.

One aspect of the present invention pertains to methods for thetreatment of a metabolic-related disorder in an individual comprisingadministering to the individual in need of such treatment atherapeutically effective amount of a compound of the present inventionor a pharmaceutical composition thereof.

One aspect of the present invention pertains to methods of decreasingfood intake of an individual comprising administering to the individualin need thereof a therapeutically effective amount of a compound of thepresent invention or pharmaceutical composition thereof.

One aspect of the present invention pertains to methods of inducingsatiety in an individual comprising administering to the individual inneed thereof a therapeutically effective amount of a compound of thepresent invention or pharmaceutical composition thereof.

One aspect of the present invention pertains to methods of controllingor decreasing weight gain of an individual comprising administering tothe individual in need thereof a therapeutically effective amount of acompound of the present invention or pharmaceutical composition thereof.

One aspect of the present invention pertains to methods of modulating aRUP3 receptor in an individual comprising contacting the receptor with acompound of the present invention. In some embodiments, the compound isan agonist for the RUP3 receptor. In some embodiments, the modulation ofthe RUP3 receptor is the treatment of a metabolic-related disorder.

Some embodiments of the present invention include a method of modulatinga RUP3 receptor in an individual comprising contacting the receptor witha compound of the present invention wherein the modulation of the RUP3receptor reduces food intake of the individual.

Some embodiments of the present invention include a method of modulatinga RUP3 receptor in an individual comprising contacting the receptor witha compound of the present invention wherein the modulation of the RUP3receptor induces satiety in the individual.

Some embodiments of the present invention include a method of modulatinga RUP3 receptor in an individual comprising contacting the receptor witha compound of the present invention wherein the modulation of the RUP3receptor controls or reduces weight gain of the individual.

One aspect of the present invention pertains to use of a compound of thepresent invention for production of a medicament for use in thetreatment of a metabolic-related disorder.

One aspect of the present invention pertains to use of a compound of thepresent invention for production of a medicament for use in decreasingfood intake in an individual.

One aspect of the present invention pertains to use of a compound of thepresent invention for production of a medicament for use of inducingsatiety in an individual.

One aspect of the present invention pertains to use of a compound of thepresent invention for production of a medicament for use in controllingor decreasing weight gain in an individual.

One aspect of the present invention pertains to a compound of thepresent invention for use in a method of treatment of the human oranimal body by therapy.

One aspect of the present invention pertains to a compound of thepresent invention for use in a method of treatment of ametabolic-related disorder of the human or animal body by therapy.

In some embodiments the individual is a mammal. In some embodiments themammal is a human.

Some embodiments of the present invention pertain to methods wherein thehuman has a body mass index of about 18.5 to about 45. In someembodiments, the human has a body mass index of about 25 to about 45. Insome embodiments, the human has a body mass index of about 30 to about45. In some embodiments, the human has a body mass index of about 35 toabout 45.

In some embodiments, the metabolic-related disorder is hyperlipidemia,type 1 diabetes, type 2 diabetes mellitus, idiopathic type 1 diabetes(Type 1b), latent autoimmune diabetes in adults (LADA), early-onset type2 diabetes (EOD), youth-onset atypical diabetes (YOAD), maturity onsetdiabetes of the young (MODY), malnutrition-related diabetes, gestationaldiabetes, coronary heart disease, ischemic stroke, restenosis afterangioplasty, peripheral vascular disease, intermittent claudication,myocardial infarction (e.g. necrosis and apoptosis), dyslipidemia,post-prandial lipemia, conditions of impaired glucose tolerance (IGT),conditions of impaired fasting plasma glucose, metabolic acidosis,ketosis, arthritis, obesity, osteoporosis, hypertension, congestiveheart failure, left ventricular hypertrophy, peripheral arterialdisease, diabetic retinopathy, macular degeneration, cataract, diabeticnephropathy, glomerulosclerosis, chronic renal failure, diabeticneuropathy, metabolic syndrome, syndrome X, premenstrual syndrome,coronary heart disease, angina pectoris, thrombosis, atherosclerosis,myocardial infarction, transient ischemic attacks, stroke, vascularrestenosis, hyperglycemia, hyperinsulinemia, hyperlipidemia,hypertrygliceridemia, insulin resistance, impaired glucose metabolism,conditions of impaired glucose tolerance, conditions of impaired fastingplasma glucose, obesity, erectile dysfunction, skin and connectivetissue disorders, foot ulcerations and ulcerative colitis, endothelialdysfunction and impaired vascular compliance.

In some embodiments, the metabolic-related disorder is type I diabetes,type II diabetes, inadequate glucose tolerance, insulin resistance,hyperglycemia, hyperlipidemia, hypertriglyceridemia,hypercholesterolemia, dyslipidemia or syndrome X. In some embodiments,the metabolic-related disorder is type II diabetes. In some embodiments,the metabolic-related disorder is hyperglycemia. In some embodiments,the metabolic-related disorder is hyperlipidemia. In some embodiments,the metabolic-related disorder is hypertriglyceridemia. In someembodiments, the metabolic-related disorder is type I diabetes. In someembodiments, the metabolic-related disorder is dyslipidemia. In someembodiments, the metabolic-related disorder is syndrome X.

One aspect of the present invention pertains to a method of producing apharmaceutical composition comprising admixing at least one compound, asdescribed herein, and a pharmaceutically acceptable carrier.

Applicant reserves the right to exclude any one or more of the compoundsfrom any of the embodiments of the invention. Applicant additionallyreserves the right to exclude any disease, condition or disorder fromany of the embodiments of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A shows RT-PCR analysis of RUP3 expression in human tissues. Atotal of twenty-two (22) human tissues were analyzed.

FIG. 1B shows the cDNA Dot-Blot analysis of RUP3 expression in humantissues.

FIG. 1C shows analysis of RUP3 by RT-PCR with isolated human pancreaticislets of Langerhans.

FIG. 1D shows analysis of RUP3 expression with cDNAs of rat origin byRT-PCR.

FIG. 2A shows a polyclonal anti-RUP3 antibody prepared in Rabbits.

FIG. 2B shows the expression of RUP3 in insulin-producing P cells ofpancreatic islets.

FIG. 3 shows in vitro functional activities of RUP3.

FIG. 4 shows a RUP3 RNA blot.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

The scientific literature that has evolved around receptors has adopteda number of terms to refer to ligands having various effects onreceptors. For clarity and consistency, the following definitions willbe used throughout this patent document.

AGONISTS shall mean moieties that interact and activate the receptor,such as the RUP3 receptor and initiates a physiological orpharmacological response characteristic of that receptor. For example,when moieties activate the intracellular response upon binding to thereceptor, or enhance GTP binding to membranes.

The term ANTAGONISTS is intended to mean moieties that competitivelybind to the receptor at the same site as agonists (for example, theendogenous ligand), but which do not activate the intracellular responseinitiated by the active form of the receptor, and can thereby inhibitthe intracellular responses by agonists or partial agonists. Antagonistsdo not diminish the baseline intracellular response in the absence of anagonist or partial agonist.

Chemical Group, Moiety or Radical:

The term “C₁₋₄ acyl” refers to a C₁₋₆ alkyl radical attached directly tothe carbon of a carbonyl group wherein the definition for alkyl is asdescribed herein; some examples include, but not limited to, acetyl,propionyl, n-butanoyl, iso-butanoyl, sec-butanoyl, t-butanoyl (alsoreferred to as pivaloyl) and the like.

The term “C₁₋₄ acylsulfonamide” refers to a C₁₋₄ acyl attached directlyto the nitrogen of the sulfonamide, wherein the definitions for C₁₋₄acyl and sulfonamide have the same meaning as described herein, and aC₁₋₄ acylsulfonamide group can be represented by the following formula:

Some embodiments of the present invention are when acylsulfonamide is aC₁₋₃ acylsulfonamide, some embodiments are C₁₋₂ acylsulfonamide and someembodiments are C₁ acylsulfonamide. Examples of an acylsulfonamide groupinclude, but not limited to, acetylsulfamoyl [—S(═O)₂NHC(═O)Me],propionylsulfamoyl [—S(═O)₂NHC(═O)Et], isobutyrylsulfamoyl,butyrylsulfamoyl, and the like.

The term “C₁₋₄ alkoxy” refers to an alkyl radical, as defined herein,attached directly to an oxygen atom (i.e., —O—C₁₋₄ alkyl). Examplesinclude methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, t-butoxy,iso-butoxy, sec-butoxy and the like.

The term “C₁₋₄ alkyl” refers to a straight or branched carbon radicalcontaining 1 to 4 carbons, some embodiments are 1 to 3 carbons, someembodiments are 1 to 2 carbons. Examples of an alkyl include, but notlimited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl,t-butyl, sec-butyl, and the like.

The term “C₁₋₄ alkylamino” refers to one alkyl radical attached directlyto an amino radical (—HN—C₁₋₄ alkyl) wherein the alkyl radical has thesame meaning as described herein. Some examples include, but not limitedto, methylamino (i.e., —HNCH₃), ethylamino, n-propylamino,iso-propylamino, n-butylamino, sec-butylamino, iso-butylamino,t-butylamino, and the like.

The term “C₁₋₄ alkylcarboxamide” or “C₁₋₄ alkylcarboxamido” refers to asingle C₁₋₄ alkyl group attached to the nitrogen of an amide group,wherein alkyl has the same definition as described herein. The C₁₋₄alkylcarboxamido may be represented by the following:

Examples include, but not limited to, N-methylcarboxamide,N-ethylcarboxamide, N-n-propylcarboxamide, N-iso-propylcarboxamide,N-n-butylcarboxamide, N-sec-butylcarboxamide, N-iso-butylcarboxamide,N-t-butylcarboxamide and the like.

The term “C₁₋₄ alkylsulfonyl” refers to a alkyl radical attached to asulfone radical of the formula: —S(O)₂— wherein the alkyl radical hasthe same definition as described herein. Examples include, but notlimited to, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl,iso-propylsulfonyl, n-butylsulfonyl, sec-butylsulfonyl,iso-butylsulfonyl, t-butyl, and the like.

The term “C₁₋₄ alkylthio” refers to a alkyl radical attached to asulfide of the formula: —S— wherein the alkyl radical has the samedefinition as described herein. Examples include, but not limited to,methylsulfanyl (i.e., CH₃S—), ethylsulfanyl, n-propylsulfanyl,iso-propylsulfanyl, n-butylsulfanyl, sec-butylsulfanyl,iso-butylsulfanyl, t-butyl, and the like.

The term “C₂₋₄ alkynyl” refers to a radical containing 2 to 4 carbonsand at least one carbon-carbon triple bond (—C≡C—), some embodiments are2 to 3 carbons, and some embodiments have 2 carbons (—C≡CH). Examples ofa C₂₋₄ alkynyl include, but not limited to, ethynyl, 1-propynyl,2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, and the like. The term C₂₋₄alkynyl includes di- and tri-ynes.

The term “amino” refers to the group —NH₂.

The term “carbo-C₁₋₆-alkoxy” refers to an alkoxy group attached directlyto the carbon of a carbonyl and can be represented by the formula—C(═O)O—C₁₋₆-alkyl, wherein the C₁₋₆ alkyl group is as defined herein.In some embodiments, the carbo-C₁₋₆-alkoxy group is further bonded to anitrogen atom and together form a carbamate group (e.g.,NC(═O)O—C₁₋₆-alkyl). Examples of the carbo-C₁₋₆-alkoxy group include,but not limited to, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,iso-propoxycarbonyl, butoxycarbonyl, sec-butoxycarbonyl,iso-butoxycarbonyl, t-butoxycarbonyl, n-pentoxycarbonyl,iso-pentoxycarbonyl, t-pentoxycarbonyl, neo-pentoxycarbonyl,n-hexyloxycarbonyl, and the like.

The term “cyano” refers to the group —CN.

The term “C₃₋₅ cycloalkyl” refers to a saturated ring radical containing3 to 5 carbons; some embodiments contain 3 to 4 carbons; someembodiments contain 3 carbons. Examples include cyclopropyl, cyclobutyl,cyclopentyl, and the like.

The term “C₃₋₅-cycloalkoxy” refers to a cycloalkyl, as defined herein,attached directly to an oxygen atom (i.e., —O—C₃₋₅ cycloalkyl). Examplesinclude, but not limited to, cyclopropoxy, cyclobutoxy, cyclopentoxy,and the like.

The term “di-C₁₋₄-dialkylamino” refers to an amino group substitutedwith two of the same or different C₁₋₄ alkyl radicals wherein alkylradical has the same definition as described herein. Some examplesinclude, but not limited to, dimethylamino, methylethylamino,diethylamino, methylpropylamino, methylisopropylamino, ethylpropylamino,ethylisopropylamino, dipropylamino, propylisopropylamino and the like.

The term “di-C₁₋₄-alkylcarboxamide” or “di-C₁₋₄-alkylcarboxamido” refersto two C₁₋₄ alkyl radicals, that are the same or different, attached toan amide group, wherein alkyl has the same definition as describedherein. A di-C₁₋₄-alkylcarboxamido can be represented by the followinggroup:

wherein C₁₋₄ has the same definition as described herein. Examples of adialkylcarboxamide include, but not limited to, N,N-dimethylcarboxamide,N-methyl-N-ethylcarboxamide, N,N-diethylcarboxamide,N-methyl-N-isopropylcarboxamide, and the like.

The term “halogen” or “halo” refers to to a fluoro, chloro, bromo oriodo group.

The term “heterocyclyl” refers to a non-aromatic carbon ring (i.e.,cycloalkyl or cycloalkenyl) wherein one, two or three ring carbons arereplaced by a heteroatom selected from, but not limited to, the groupconsisting of —O—, —S—, —S(═O)—, —S(═O)₂—, and —NH—, and the ring carbonatoms are optionally substituted with oxo or thiooxo thus forming acarbonyl or thiocarbonyl group respectively. The heterocyclic group canbe a 3, 4, 5 or 6-member containing ring. Examples of a heterocyclicgroup, include but not limited to, aziridin-1-yl, aziridin-2-yl,azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, piperidin-1-yl,piperidin-4-yl, morpholin-4-yl, piperzin-1-yl, piperzin-4-yl,pyrrolidin-1-yl, pyrrolidin-3-yl, [1,3]-dioxolan-2-yl and the like.

The term “hydroxyl” refers to the group —OH.

The term “oxadiazolyl” refers to the group represented by the followingformulae:

The term “oxo” refers generally to a double bonded oxygen; typically“oxo” is a substitution on a carbon and together form a carbonyl group.

The term “phosphonooxy” refers to a group of the formula —OP(O)(OH)₂ andcan be represented by the following chemical structure:

The term “pyrimidinyl” refers to the group represented by the followingformulae:

The term “sulfonamide” refers to the group —S(═O)₂NH₂.

COMPOSITION shall mean a material comprising at least two compounds ortwo components; for example, and without limitation, a PharmaceuticalComposition is a Composition comprising a compound of the presentinvention and a pharmaceutically acceptable carrier.

COMPOUND EFFICACY shall mean a measurement of the ability of a compoundto inhibit or stimulate receptor functionality, as opposed to receptorbinding affinity.

CONTACT or CONTACTING shall mean bringing the indicated moietiestogether, whether in an in vitro system or an in vivo system. Thus,“contacting” a RUP3 receptor with a compound of the invention includesthe administration of a compound of the present invention to anindividual, for example a human, having a RUP3 receptor, as well as, forexample, introducing a compound of the invention into a samplecontaining a cellular or more purified preparation containing a RUP3receptor.

IN NEED OF TREATMENT as used herein refers to a judgment made by acaregiver (e.g. physician, nurse, nurse practitioner, etc. in the caseof humans; veterinarian in the case of animals, including non-humanmammals) that an individual or animal requires or will benefit fromtreatment. This judgment is made based on a variety of factors that arein the realm of a caregiver's expertise, but that includes the knowledgethat the individual is ill, or will be ill, as the result of a disease,condition or disorder that is treatable by the compounds of theinvention. The term “treatment” also refers in the alternative to“prophylaxis.” Therefore, in general, “in need of treatment” refers tothe judgment of the caregiver that the individual is already ill,accordingly, the compounds of the present invention are used toalleviate, inhibit or ameliorate the disease, condition or disorder.Furthermore, the phrase also refers, in the alternative, to the judgmentmade by the caregiver that the individual will become ill. In thiscontext, the compounds of the invention are used in a protective orpreventive manner.

INDIVIDUAL as used herein refers to any animal, including mammals,preferably mice, rats, other rodents, rabbits, dogs, cats, swine,cattle, sheep, horses, or primates, and most preferably humans.

INHIBIT or INHIBITING, in relationship to the term “response” shall meanthat a response is decreased or prevented in the presence of a compoundas opposed to in the absence of the compound.

INVERSE AGONISTS shall mean moieties that bind the endogenous form ofthe receptor or to the constitutively activated form of the receptor,and which inhibit the baseline intracellular response initiated by theactive form of the receptor below the normal base level of activitywhich is observed in the absence of agonists or partial agonists, ordecrease GTP binding to membranes. Preferably, the baselineintracellular response is inhibited in the presence of the inverseagonist by at least 30%, more preferably by at least 50%, and mostpreferably by at least 75%, as compared with the baseline response inthe absence of the inverse agonist.

LIGAND shall mean an endogenous, naturally occurring molecule specificfor an endogenous, naturally occurring receptor.

As used herein, the terms MODULATE or MODULATING shall mean to refer toan increase or decrease in the amount, quality, response or effect of aparticular activity, function or molecule.

PHARMACEUTICAL COMPOSITION shall mean a composition comprising at leastone active ingredient, whereby the composition is amenable toinvestigation or treatment of a specified, efficacious outcome in amammal (for example, without limitation, a human). Those of ordinaryskill in the art will understand and appreciate the techniquesappropriate for determining whether an active ingredient has a desiredefficacious outcome based upon the needs of the artisan.

THERAPEUTICALLY EFFECTIVE AMOUNT as used herein refers to the amount ofactive compound or pharmaceutical agent that elicits the biological ormedicinal response in a tissue, system, animal, individual or human thatis being sought by a researcher, veterinarian, medical doctor or otherclinician, which includes one or more of the following:

(1) Preventing the disease; for example, preventing a disease, conditionor disorder in an individual that may be predisposed to the disease,condition or disorder but does not yet experience or display thepathology or symptomatology of the disease,

(2) Inhibiting the disease; for example, inhibiting a disease, conditionor disorder in an individual that is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,arresting further development of the pathology and/or symptomatology),and

(3) Ameliorating the disease; for example, ameliorating a disease,condition or disorder in an individual that is experiencing ordisplaying the pathology or symptomatology of the disease, condition ordisorder (i.e., reversing the pathology and/or symptomatology).

Compounds of the Present Invention:

One aspect of the present invention encompasses certain substitutedpyridinyl and pyrimidinyl derivatives as shown in Formula (Ia):

or a pharmaceutically acceptable salt, hydrate or solvate thereof;wherein X, Y, Z, R₁, R₂, R₃, R₄, R₅, R₆ and R₇ have the same definitionsas described herein, supra and infra.

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, may also beprovided in combination in a single embodiment. Conversely, variousfeatures of the invention, which are, for brevity, described in thecontext of a single embodiment, may also be provided separately or inany suitable subcombination. All combinations of the embodimentspertaining to the chemical groups represented by the variables (e.g.,R₁, R₂, R₃, R₄, R₅, R₆, R₇, X, Y, and Z) contained within the genericchemical formulae described herein [e.g. (Ia), (IIa), (IIc), (IIe),(IIg), etc.] are specifically embraced by the present invention just asif they were explicitly disclosed, to the extent that such combinationsembrace compounds that result in stable compounds (ie., compounds thatcan be isolated, characterized and tested for biological activity). Inaddition, all subcombinations of the chemical groups listed in theembodiments describing such variables, as well as all subcombinations ofuses and medical indications described herein, are also specificallyembraced by the present invention just as if each of such subcombinationof chemical groups and subcomination of uses and medical indicationswere explicitly disclosed herein.

As used herein, “substituted” indicates that at least one hydrogen atomof the chemical group is replaced by a non-hydrogen substituent orgroup, the non-hydrogen substituent or group can be monovalent ordivalent. When the substituent or group is divalent, then it isunderstood that this group is further substituted with anothersubstituent or group. When a chemical group herein is “substituted” itmay have up to the full valance of substitution; for example, a methylgroup can be substituted by 1, 2, or 3 substituents, a methylene groupcan be substituted by 1 or 2 substituents, a phenyl group can besubstituted by 1, 2, 3, 4, or 5 substituents, a naphthyl group can besubstituted by 1, 2, 3, 4, 5, 6, or 7 substituents and the like.Likewise, “substituted with one or more substituents” refers to thesubstitution of a group with one substituent up to the total number ofsubstituents physically allowed by the group. Further, when a group issubstituted with more than one group they can be identical or they canbe different.

It is understood and appreciated that compounds of the invention mayhave one or more chiral centers, and therefore can exist as enantiomersand/or diastereomers. The invention is understood to extend to andembrace all such enantiomers, diastereomers and mixtures thereof,including, but not limited to, racemates. Accordingly, some embodimentsof the present invention pertain to compounds that are R enantiomers.Further, some embodiments of the present invention pertain to compoundsthat are S enantiomers. When more than one chiral center is present, forexample two chiral centers then, some embodiments of the presentinvention are compounds that are RS or SR enantiomers. In furtherembodiments, compounds of the present invention are RR or SSenantiomers. It is understood that compounds of Formula (Ia) andformulae used throughout this disclosure are intended to represent allindividual enantiomers and mixtures thereof, unless stated or shownotherwise.

Compounds of the invention can also include tautomeric forms, such asketo-enol tautomers, and the like. Tautomeric forms can be inequilibrium or sterically locked into one form by appropriatesubstitution. It is understood that the various tautomeric forms arewithin the scope of the compounds of the present invention.

Compounds of the invention can also include all isotopes of atomsoccurring in the intermediates and/or final compounds. Isotopes includethose atoms having the same atomic number but different mass numbers.For example, isotopes of hydrogen include deuterium and tritium.

Some embodiments of the present invention pertain to compounds wherein Xis N.

Some embodiments of the present invention pertain to compounds wherein Xis CR₈. In some embodiments, R₈ is H or F.

Some embodiments of the present invention pertain to compounds wherein Yis NH.

Some embodiments of the present invention pertain to compounds wherein Yis O.

Some embodiments of the present invention pertain to compounds wherein Zis CH.

Some embodiments of the present invention pertain to compounds wherein Zis N.

Some embodiments of the present invention pertain to compounds whereinR₁ is carbo-C₁₋₆-alkoxy optionally substituted with C₃₋₅ cycloalkyl.

Some embodiments of the present invention pertain to compounds whereinR₁ is selected form the group consisting of C(O)OCH₂CH₃, C(O)OCH(CH₃)₂,C(O)OCH(CH₃)(CH₂CH₃), C(O)OCH₂-cyclopropyl, C(O)OCH(CH₃)(cyclopropyl),and C(O)OCH(CH₂CH₃)₂.

Some embodiments of the present invention pertain to compounds whereinR₁ is selected form the group consisting of C(O)OCH₂CH₃, C(O)OCH(CH₃)₂,C(O)OCH(CH₃)(CH₂CH₃), C(O)OCH₂-cyclopropyl andC(O)OCH(CH₃)(cyclopropyl); these can be represented by the respectiveformulae:

Some embodiments of the present invention pertain to compounds whereinR₁ is oxadiazolyl optionally substituted with one C₁₋₄ alkyl group.

Some embodiments of the present invention pertain to compounds whereinR₁ is 5-isopropyl-[1,2,4]oxadiazol-3-yl.

Some embodiments of the present invention pertain to compounds whereinR₁ is pyrimidinyl optionally substituted with one C₁₋₄ alkoxy group.

Some embodiments of the present invention pertain to compounds whereinR₁ is 5-methoxy-pyrimidin-2-yl.

Some embodiments of the present invention pertain to compounds whereinR₂ is H.

Some embodiments of the present invention pertain to compounds whereinR₂ is CH₃.

Some embodiments of the present invention pertain to compounds whereinR₃ is C₁₋₄ alkoxy.

Some embodiments of the present invention pertain to compounds whereinR₃ is OCH₃ or OCH₂CH₃.

Some embodiments of the present invention pertain to compounds whereinR₃ is OCH₃.

Some embodiments of the present invention pertain to compounds whereinR₃ is OH or O—C≡CH.

Some embodiments of the present invention pertain to compounds whereinR₄ is selected from the group consisting of H, OCH₃, CH₃, CH₂CH₃, F, Cland C≡CH.

Some embodiments of the present invention pertain to compounds whereinR₄ is CH₃.

Some embodiments of the present invention pertain to compounds whereinR₅ is selected from the group consisting of OCH₂CH₂CH₃, OCH₂CH₂CH₂OH,S(O)₂CH₃, CH₂CH₂S(O)₂CH₃, NHCH₂CH₂OH, cyano, CH₂CH₂OCH₃, CH₂CH₂OH,CH₂CH₂CH(CH₃)OH, CH₂CH₂OP(O)(OH)₂, S(O)₂NHC(O)CH₂CH₃,CH₂CH₂O-cyclopropyl, NHCH₂CH₂OCH₃, OCH₂CH₂S(O)₂CH₃, NHCH₂CH(CH₃)OH,CH₂CH₂CH₂OH, CH₂CH₂CH₂OP(O)(OH)₂, NHCH₂CH(CH₃)S(O)₂CH₃,N(CH₃)CH₂CH(CH₃)S(O)₂CH₃, 3-methanesulfonyl-pyrrolidin-1-yl,3-methanesulfonyl-piperidin-1-yl, CH₂C(O)N(CH₃)₂,3-methanesulfonyl-azetidin-1-yl, CH₂C(O)NHCH₂CH₂OH, SCH₂CH₂OH,S(O)₂CH₂CH₂OP(O)(OH)₂, S(O)₂CH₂CH₃, NHCH₂CH(OH)CH₂OH, S(O)₂CH₂CH₂OH,OCH₂CH₂OP(O)(OH)₂, OCH₂CH₂CH₂OP(O)(OH)₂, S(O)₂NH₂, CH₃, SCH₂CH₂CH₃,S(O)₂CH₂CH₂CH₃, SCH₂CH₃, SCH(CH₃)₂, S(O)₂CH(CH₃)₂, and CH₂OH.

Some embodiments of the present invention pertain to compounds whereinR₅ is selected from the group consisting of OCH₂CH₂CH₃, OCH₂CH₂CH₂OH,S(O)₂CH₃, CH₂CH₂S(O)₂CH₃, NHCH₂CH₂OH, cyano, CH₂CH₂OCH₃, CH₂CH₂OH,CH₂CH₂CH(CH₃)OH, CH₂CH₂OP(O)(OH)₂, S(O)₂NHC(O)CH₂CH₃,CH₂CH₂O-cyclopropyl, NHCH₂CH₂OCH₃, OCH₂CH₂S(O)₂CH₃, NHCH₂CH(CH₃)OH,CH₂CH₂CH₂OH, CH₂CH₂CH₂OP(O)(OH)₂, NHCH₂CH(CH₃)S(O)₂CH₃,N(CH₃)CH₂CH(CH₃)S(O)₂CH₃, 3-methanesulfonyl-pyrrolidin-1-yl,3-methanesulfonyl-piperidin-1-yl, CH₂C(O)N(CH₃)₂,3-methanesulfonyl-azetidin-1-yl, CH₂C(O)NHCH₂CH₂OH, SCH₂CH₂OH,S(O)₂CH₂CH₂OP(O)(OH)₂, S(O)₂CH₂CH₃, NHCH₂CH(OH)CH₂OH, S(O)₂CH₂CH₂OH,OCH₂CH₂OP(O)(OH)₂, OCH₂CH₂CH₂OP(O)(OH)₂ and S(O)₂NH₂.

Some embodiments of the present invention pertain to compounds whereinR₅ is selected from the group consisting of OCH₂CH₂CH₂OH, S(O)₂CH₃,CH₂CH₂S(O)₂CH₃, NHCH₂CH₂OH, cyano, CH₂CH₂OH, CH₂CH₂CH(CH₃)OH,CH₂CH₂OP(O)(OH)₂, S(O)₂NHC(O)CH₂CH₃, CH₂CH₂CH₂OH, S(O)₂CH₂CH₃,NHCH₂CH(OH)CH₂OH, amino, NHCH₂CH₃, NHCH(CH₃)₂ and NHCH(CH₃)CH₂CH₃.

Some embodiments of the present invention pertain to compounds whereinR₅ is a group other than —CH₂—R₁₀, wherein R₁₀ is selected from thegroup consisting of C₁₋₄ alkylcarboxamide, C₁₋₄ alkylsulfonyl,di-C₁₋₄-alkylcarboxamide, and phosphonooxy. In some embodiments, R₅ is agroup other than —CH₂—R₁₀, wherein R₁₀ is C₁₋₄ alkylcarboxamide. In someembodiments, R₅ is a group other than —CH₂—R₁₀, wherein R₁₀ is C₁₋₄alkylsulfonyl. In some embodiments, R₅ is a group other than —CH₂—R₁₀,wherein R₁₀ is di-C₁₋₄-alkylcarboxamide. In some embodiments, R₅ is agroup other than —CH₂—R₁₀, wherein R₁₀ is phosphonooxy.

Some embodiments of the present invention pertain to compounds whereinR₅ is selected from the group consisting of OCH₂CH₂CH₃, OCH₂CH₂CH₂OH,S(O)₂CH₃, CH₂CH₂S(O)₂CH₃, NHCH₂CH₂OH, cyano, CH₂CH₂OCH₃, CH₂CH₂OH,CH₂CH₂CH(CH₃)OH, CH₂CH₂OP(O)(OH)₂, S(O)₂NHC(O)CH₂CH₃,CH₂CH₂O-cyclopropyl, NHCH₂CH₂OCH₃, OCH₂CH₂S(O)₂CH₃, NHCH₂CH(CH₃)OH,CH₂CH₂CH₂OH, CH₂CH₂CH₂OP(O)(OH)₂, NHCH₂CH(CH₃)S(O)₂CH₃,N(CH₃)CH₂CH(CH₃)S(O)₂CH₃, 3-methanesulfonyl-pyrrolidin-1-yl,3-methanesulfonyl-piperidin-1-yl, 3-methanesulfonyl-azetidin-1-yl,CH₂C(O)NHCH₂CH₂OH, SCH₂CH₂OH, S(O)₂CH₂CH₂OP(O)(OH)₂, S(O)₂CH₂CH₃,NHCH₂CH(OH)CH₂OH, S(O)₂CH₂CH₂OH, OCH₂CH₂OP(O)(OH)₂, OCH₂CH₂CH₂OP(O)(OH)₂and S(O)₂NH₂.

Some embodiments of the present invention pertain to compounds whereinR₅ is a group of Formula (A):

wherein “m”, “n” and “q” are each independently 0, 1, 2 or 3; “r” is 0,1 or 2; and “t” is 0 or 1. In some embodiments, “m” and “n” are eachindependently 0 or 1. In some embodiments, “q” is 0 or 1 and “r” is 1 or2. In some embodiments, “t” is 1. In some embodiments, “t” is 0.

Some embodiments of the present invention pertain to compounds whereinR₅ is a group of Formula (B):

wherein “m”, “n”, “q” and “r” are as described herein, supra and infra.

Some embodiments of the present invention pertain to compounds whereinR₅ is selected from the group consisting of:

Some embodiments of the present invention pertain to compounds whereinR₆ is H.

Some embodiments of the present invention pertain to compounds whereinR₆ is F.

Some embodiments of the present invention pertain to compounds whereinR₇ is H.

Some embodiments of the present invention pertain to compounds whereinR₇ is CH₃.

Some embodiments of the present invention pertain to compounds havingFormula (IIa):

or a pharmaceutically acceptable salt, solvate or hydrate thereof;

wherein:

Y is NH or O;

R₁ is carbo-C₁₋₆-alkoxy optionally substituted with C₃₋₅ cycloalkyl;

R₂ is H or CH₃;

R₃ is C₁₋₄ alkoxy;

R₄ is selected from the group consisting of H, OCH₃, CH₃, CH₂CH₃, F andCl;

R₅ is selected from the group consisting of OCH₂CH₂CH₃, OCH₂CH₂CH₂OH,S(O)₂CH₃, CH₂CH₂S(O)₂CH₃, NHCH₂CH₂OH, cyano, CH₂CH₂OCH₃, CH₂CH₂OH,CH₂CH₂CH(CH₃)OH, CH₂CH₂OP(O)(OH)₂, S(O)₂NHC(O)CH₂CH₃,CH₂CH₂O-cyclopropyl, NHCH₂CH₂OCH₃, OCH₂CH₂S(O)₂CH₃, NHCH₂CH(CH₃)OH,CH₂CH₂CH₂OH, CH₂CH₂CH₂OP(O)(OH)₂, NHCH₂CH(CH₃)S(O)₂CH₃,N(CH₃)CH₂CH(CH₃)S(O)₂CH₃, 3-methanesulfonyl-pyrrolidin-1-yl,3-methanesulfonyl-piperidin-1-yl, CH₂C(O)N(CH₃)₂,3-methanesulfonyl-azetidin-1-yl, CH₂C(O)NHCH₂CH₂OH, SCH₂CH₂OH,S(O)₂CH₂CH₂OP(O)(OH)₂, S(O)₂CH₂CH₃, NHCH₂CH(OH)CH₂OH, S(O)₂CH₂CH₂OH,OCH₂CH₂OP(O)(OH)₂, OCH₂CH₂CH₂OP(O)(OH)₂ and S(O)₂NH₂;

R₆ is H or F; and

R₇ is H or CH₃

Some embodiments of the present invention pertain to compounds havingFormula (IIa):

or a pharmaceutically acceptable salt, solvate or hydrate thereof;

wherein:

Y is NH or O;

R₁ is carbo-C₁₋₆-alkoxy optionally substituted with C₃₋₅ cycloalkyl;

R₂ is H or CH₃;

R₃ is C₁₋₄ alkoxy;

R₄ is selected from the group consisting of H, OCH₃, CH₃, CH₂CH₃, F andCl;

R₅ is selected from the group consisting of OCH₂CH₂CH₂OH, S(O)₂CH₃,CH₂CH₂S(O)₂CH₃, NHCH₂CH₂OH, cyano, CH₂CH₂OH, CH₂CH₂CH(CH₃)OH,CH₂CH₂OP(O)(OH)₂, S(O)₂NHC(O)CH₂CH₃, CH₂CH₂CH₂OH, S(O)₂CH₂CH₃,NHCH₂CH(OH)CH₂OH and S(O)₂NH₂;

R₆ is H or F; and

R₇ is H or CH₃.

Some embodiments of the present invention pertain to compounds havingFormula (IIc):

or a pharmaceutically acceptable salt, solvate or hydrate thereof;

wherein:

R₁ is carbo-C₁₋₆-alkoxy optionally substituted with C₃₋₅ cycloalkyl;

R₂ is H or CH₃;

R₃ is C₁₋₄ alkoxy;

R₄ is selected from the group consisting of H, OCH₃, CH₃, CH₂CH₃, F andCl;

R₅ is selected from the group consisting of OCH₂CH₂CH₃, OCH₂CH₂CH₂OH,S(O)₂CH₃, CH₂CH₂S(O)₂CH₃, NHCH₂CH₂OH, cyano, CH₂CH₂OCH₃, CH₂CH₂OH,CH₂CH₂CH(CH₃)OH, CH₂CH₂OP(O)(OH)₂, S(O)₂NHC(O)CH₂CH₃,CH₂CH₂O-cyclopropyl, NHCH₂CH₂OCH₃, OCH₂CH₂S(O)₂CH₃, NHCH₂CH(CH₃)OH,CH₂CH₂CH₂OH, CH₂CH₂CH₂OP(O)(OH)₂, NHCH₂CH(CH₃)S(O)₂CH₃,N(CH₃)CH₂CH(CH₃)S(O)₂CH₃, 3-methanesulfonyl-pyrrolidin-1-yl,3-methanesulfonyl-piperidin-1-yl, CH₂C(O)N(CH₃)₂,3-methanesulfonyl-azetidin-1-yl, CH₂C(O)NHCH₂CH₂OH, SCH₂CH₂OH,S(O)₂CH₂CH₂OP(O)(OH)₂, S(O)₂CH₂CH₃, NHCH₂CH(OH)CH₂OH, S(O)₂CH₂CH₂OH,OCH₂CH₂OP(O)(OH)₂, OCH₂CH₂CH₂OP(O)(OH)₂ and S(O)₂NH₂;

R₆ is H or F; and

R₇ is H or CH₃.

Some embodiments of the present invention pertain to compounds havingFormula (IIc):

or a pharmaceutically acceptable salt, solvate or hydrate thereof;

wherein:

R₁ is carbo-C₁₋₆-alkoxy optionally substituted with C₃₋₅ cycloalkyl;

R₂ is H or CH₃;

R₃ is C₁₋₄ alkoxy;

R₄ is selected from the group consisting of H, OCH₃, CH₃, CH₂CH₃, F andCl;

R₅ is selected from the group consisting of OCH₂CH₂CH₂OH, S(O)₂CH₃,CH₂CH₂S(O)₂CH₃, NHCH₂CH₂OH, cyano, CH₂CH₂OH, CH₂CH₂CH(CH₃)OH,CH₂CH₂OP(O)(OH)₂, S(O)₂NHC(O)CH₂CH₃, CH₂CH₂CH₂OH, S(O)₂CH₂CH₃,NHCH₂CH(OH)CH₂OH and S(O)₂NH₂;

R₆ is H or F; and

R₇ is H or CH₃.

Some embodiments of the present invention pertain to compounds havingFormula (IIe):

or a pharmaceutically acceptable salt, solvate or hydrate thereof;

wherein:

R₁ is carbo-C₁₋₆-alkoxy optionally substituted with C₃₋₅ cycloalkyl;

R₂ is H or CH₃;

R₃ is C₁₋₄ alkoxy;

R₄ is selected from the group consisting of H, OCH₃, CH₃, CH₂CH₃, F andCl;

R₅ is selected from the group consisting of OCH₂CH₂CH₃, OCH₂CH₂CH₂OH,S(O)₂CH₃, CH₂CH₂S(O)₂CH₃, NHCH₂CH₂OH, cyano, CH₂CH₂OCH₃, CH₂CH₂OH,CH₂CH₂CH(CH₃)OH, CH₂CH₂OP(O)(OH)₂, S(O)₂NHC(O)CH₂CH₃,CH₂CH₂O-cyclopropyl, NHCH₂CH₂OCH₃, OCH₂CH₂S(O)₂CH₃, NHCH₂CH(CH₃)OH,CH₂CH₂CH₂OH, CH₂CH₂CH₂OP(O)(OH)₂, NHCH₂CH(CH₃)S(O)₂CH₃,N(CH₃)CH₂CH(CH₃)S(O)₂CH₃, 3-methanesulfonyl-pyrrolidin-1-yl,3-methanesulfonyl-piperidin-1-yl, CH₂C(O)N(CH₃)₂,3-methanesulfonyl-azetidin-1-yl, CH₂C(O)NHCH₂CH₂OH, SCH₂CH₂OH,S(O)₂CH₂CH₂OP(O)(OH)₂, S(O)₂CH₂CH₃, NHCH₂CH(OH)CH₂OH, S(O)₂CH₂CH₂OH,OCH₂CH₂OP(O)(OH)₂, OCH₂CH₂CH₂OP(O)(OH)₂ and S(O)₂NH₂;

R₆ is H or F; and

R₇ is H or CH₃.

Some embodiments of the present invention pertain to compounds havingFormula (IIe):

or a pharmaceutically acceptable salt, solvate or hydrate thereof;

wherein:

R₁ is carbo-C₁₋₆-alkoxy optionally substituted with C₃₋₅ cycloalkyl;

R₂ is H or CH₃;

R₃ is C₁₋₄ alkoxy;

R₄ is selected from the group consisting of H, OCH₃, CH₃, CH₂CH₃, F andCl;

R₅ is selected from the group consisting of OCH₂CH₂CH₂OH, S(O)₂CH₃,CH₂CH₂S(O)₂CH₃, NHCH₂CH₂OH, cyano, CH₂CH₂OH, CH₂CH₂CH(CH₃)OH,CH₂CH₂OP(O)(OH)₂, S(O)₂NHC(O)CH₂CH₃, CH₂CH₂CH₂OH, S(O)₂CH₂CH₃,NHCH₂CH(OH)CH₂OH and S(O)₂NH₂;

R₆ is H or F; and

R₇ is H or CH₃.

Some embodiments of the present invention pertain to compounds havingFormula (IIg):

or a pharmaceutically acceptable salt, solvate or hydrate thereof,

wherein:

R₁ is carbo-C₁₋₆-alkoxy optionally substituted with C₃₋₅ cycloalkyl;

R₂ is H or CH₃;

R₃ is C₁₋₄ alkoxy;

R₄ is selected from the group consisting of H, OCH₃, CH₃, CH₂CH₃, F andCl;

R₅ is selected from the group consisting of OCH₂CH₂CH₃, OCH₂CH₂CH₂OH,S(O)₂CH₃, CH₂CH₂S(O)₂CH₃, NHCH₂CH₂OH, cyano, CH₂CH₂OCH₃, CH₂CH₂OH,CH₂CH₂CH(CH₃)OH, CH₂CH₂OP(O)(OH)₂, S(O)₂NHC(O)CH₂CH₃,CH₂CH₂O-cyclopropyl, NHCH₂CH₂OCH₃, OCH₂CH₂S(O)₂CH₃, NHCH₂CH(CH₃)OH,CH₂CH₂CH₂OH, CH₂CH₂CH₂OP(O)(OH)₂, NHCH₂CH(CH₃)S(O)₂CH₃,N(CH₃)CH₂CH(CH₃)S(O)₂CH₃, 3-methanesulfonyl-pyrrolidin-1-yl,3-methanesulfonyl-piperidin-1-yl, CH₂C(O)N(CH₃)₂,3-methanesulfonyl-azetidin-1-yl, CH₂C(O)NHCH₂CH₂OH, SCH₂CH₂OH,S(O)₂CH₂CH₂OP(O)(OH)₂, S(O)₂CH₂CH₃, NHCH₂CH(OH)CH₂OH, S(O)₂CH₂CH₂OH,OCH₂CH₂OP(O)(OH)₂, OCH₂CH₂CH₂OP(O)(OH)₂ and S(O)₂NH₂;

R₆ is H or F; and

R₇ is H or CH₃

Some embodiments of the present invention pertain to compounds havingFormula (IIg):

or a pharmaceutically acceptable salt, solvate or hydrate thereof;

wherein:

R₁ is carbo-C₁₋₆-alkoxy optionally substituted with C₃₋₅ cycloalkyl;

R₂ is H or CH₃;

R₃ is C₁₋₄ alkoxy;

R₄ is selected from the group consisting of H, OCH₃, CH₃, CH₂CH₃, F andCl;

R₅ is selected from the group consisting of OCH₂CH₂CH₂OH, S(O)₂CH₃,CH₂CH₂S(O)₂CH₃, NHCH₂CH₂OH, cyano, CH₂CH₂OH, CH₂CH₂CH(CH₃)OH,CH₂CH₂OP(O)(OH)₂, S(O)₂NHC(O)CH₂CH₃, CH₂CH₂CH₂OH, S(O)₂CH₂CH₃,NHCH₂CH(OH)CH₂OH and S(O)₂NH₂;

R₆ is H or F; and

R₇ is H or CH₃.

Some embodiments of the present invention pertain to compounds havingFormula (IIi):

or a pharmaceutically acceptable salt, solvate or hydrate thereof;

wherein:

“m” and “n” are each independently 0 or 1;

“q” is 0 or 1;

“r” is 1 or 2;

X is N or O;

R₁ is carbo-C₁₋₆-alkoxy optionally substituted with C₃₋₅ cycloalkyl;

R₂ is H or CH₃;

R₃ is C₁₋₄ alkoxy;

R₄ is selected from the group consisting of H, OCH₃, CH₃, CH₂CH₃, F andCl;

R₆ is H or F; and

R₇ is H or CH₃.

Some embodiments of the present invention include every combination ofone or more compounds selected from the following group in Table A:TABLE A Cmpd No. Structure Chemical Name 1

4-[2-(2-Fluoro-4-propoxy- phenylamino)-3-methoxy-pyridin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester 2

4-{2-[2-Fluoro-4-(2-hydroxy-ethyl)- phenylamino]-3 -methoxy-pyridin-4-yloxy}-piperidine-1-carboxylic acid isopropyl ester 3

4-[5-Fluoro-2-(2-fluoro-4- methanesulfonyl-phenylamino)-3-methoxy-pyridin-4-yloxy]-piperidine 1-carboxylic acid isopropyl ester 4

(S)-4-{2-[2-Ethyl-4-(2- methanesulfonyl-ethyl)-phenylamino]-3-methoxy-pyridin-4-yloxy}-2- methyl-piperidine-1-carboxylic acidisopropyl ester 5

4-{5-Fluoro-2-[6-(2-hydroxy-ethoxy)- 2-methyl-pyridin-3-ylamino]-3-methoxy-pyridin-4-yloxy}-piperidine- 1-carboxylic acid isopropyl ester 6

4-{2-[2-Fluoro-4-(2-methanesulfonyl- ethyl)-phenylamino]-3-methoxy-pyridin-4-yloxy}-piperidine-1- carboxylic acid isopropyl ester 7

4-{2-[6-(2-Hydroxy-ethylamino)-2- methyl-pyridin-3-ylamino]-3-methoxy-pyridin-4-yloxy}-piperidine- 1-carboxylic acid isopropyl ester 8

4-[2-(4-Cyano-2-fluoro-phenylamino)- 3-methoxy-pyridin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester 9

4-[2-(2-Chloro-4-cyano- phenylamino)-3-methoxy-pyridin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester 10

4-[6-(4-Methanesulfonyl-2-methoxy- phenylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester 11

4-{5-Methoxy-6-[6-(2-methoxy- ethyl)-2-methyl-pyridin-3-ylamino]-pyrimidin-4-yloxy}-piperidine-1- carboxylic acid isopropyl ester 12

4-{2-[6-(2-Methanesulfonyl-ethyl)-2- methoxy-pyridin-3-ylamino]-3-methoxy-pyridin-4-yloxy}-piperidine- 1-carboxylic acid isopropyl ester13

4-{2-[6-(2-Methanesulfonyl-ethyl)-2- methyl-pyridin-3-ylamino]-3-methoxy-pyridin-4-yloxy}-piperidine- 1-carboxylic acid isopropyl ester14

4-{2-[6-(2-Hydroxy-ethyl)-2-methyl- pyridin-3-ylamino]-3-methoxy-pyridin-4-yloxy}-piperidine-1- carboxylic acid isopropyl ester 15

(R)-4-{2-[6-(3-Hydroxy-butyl)-2- methoxy-pyridin-3 -ylamino]-3-methoxy-pyridin-4-yloxy}-piperidine- 1-carboxylic acid isopropyl ester16

4-{2-[2-Fluoro-4-(2-hydroxy-ethoxy)- phenylamino]-3-methoxy-pyridin-4-yloxy}-piperidine-1-carboxylic acid isopropyl ester 17

4-{3-Ethoxy-2-[2-fluoro-4-(2- phosphonooxy-ethyl)-phenylamino]-pyridin-4-yloxy}-piperidine-1- carboxylic acid isopropyl ester 18

4-[3-Methoxy-2-(2-methoxy-4- propionylsulfamoyl-phenylamino)-pyridin-4-yloxy]-piperidine-1- carboxylic acid isopropyl ester 19

(S)-4-{6-[6-(2-Methanesulfonyl- ethyl)-2-methyl-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}- piperidine-1-carboxylic acid 1-cyclopropyl-ethyl ester 20

4-[2-(2,5-Difluoro-4-propoxy- phenylamino)-3-methoxy-pyridin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester 21

(2-Fluoro-4-methanesulfonyl-phenyl)-{4-[1-(5-isopropyl-[1,2,4]oxadiazol-3- yl)-piperidin-4-yloxy]-3-methoxy-pyridin-2-yl}-amine 22

(2-Fluoro-4-methanesulfonyl-phenyl)- {3-methoxy-4-[1-(5-methoxy-pyrimidin-2-yl)-piperidin-4-yloxy]- pyridin-2-yl}-amine 23

4-{2-[6-(2-Cyclopropoxy-ethyl)-2- methyl-pyridin-3-ylamino]-3-methoxy-pyridin-4-yloxy}-piperidine- 1-carboxylic acid isopropyl ester24

4-[6-(2-Fluoro-4-methanesulfonyl- phenylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester 25

4-[6-(4-Cyano-2-fluoro-phenylamino)- 5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester 26

4-[2-(2-Chloro-4-methanesulfonyl- phenylamino)-5-fluoro-3-methoxy-pyridin-4-yloxy]-piperidine-1- carboxylic acid isopropyl ester 27

4-{6-[6-(2-Hydroxy-ethyl)-2-methyl- pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1- carboxylic acid isopropyl ester 28

4-[3-Ethoxy-2-(4-methanesulfonyl-2- methoxy-phenylamino)-pyridin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester 29

4-[2-(5-Fluoro-2-methyl-4-propoxy- phenylamino)-3-methoxy-pyridin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester 30

4-{6-[6-(2-Methanesulfonyl-ethyl)-2- methyl-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}- piperidine-1-carboxylic acid isopropyl ester31

4-{5-Methoxy-6-[6-(2-methoxy- ethylamino)-2-methyl-pyridin-3-ylamino]-pyrimidin-4-yloxy}- piperidine-1-carboxylic acid isopropylester 32

4-{2-[6-(2-Methanesulfonyl-ethyl)-2- methyl-pyridin-3-ylamino]-3-methoxy-pyridin-4-yloxy}-piperidine- 1-carboxylic acid isopropyl ester33

4-[2-(2-Fluoro-4-methanesulfonyl- phenylamino)-3-hydroxy-pyridin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester 34

4-[2-(2-Chloro-4-propoxy- phenylamino)-3-methoxy-pyridin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester 35

4-{6-[6-(2-Methanesulfonyl-ethoxy)- 2-methyl-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}- piperidine-1-carboxylic acid isopropyl ester36

(S)-4-{6-[6-(2-Hydroxy-propylamino)- 2-methyl-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}- piperidine-1-carboxylic acid isopropyl ester37

4-{3-Methoxy-2-[2-methyl-6-(2- phosphonooxy-ethyl)-pyridin-3-ylamino]-pyridin-4-yloxy}-piperidine- 1-carboxylic acid isopropyl ester38

4-{6-[6-(3-Hydroxy-propyl)-2-methyl- pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1- carboxylic acid isopropyl ester 39

4-{5-Methoxy-6-[2-methyl-6-(3- phosphonooxy-propyl)-pyridin-3-ylamino]-pyrimidin-4-yloxy}- piperidine-1-carboxylic acid isopropylester 40

4-{6-[6-(2-Methanesulfonyl- ethylamino)-2-methoxy-pyridin-3-ylamino]-5-methoxy-pyrimidin-4- yloxy}-piperidine-1-carboxylic acidisopropyl ester 41

4-{2-[6-(2-Methanesulfonyl- ethylamino)-2-methyl-pyridin-3-ylamino]-3-methoxy-pyridin-4- yloxy}-piperidine-1-carboxylic acidisopropyl ester 42

4-(2-{6-[(2-Methanesulfonyl-ethyl)- methyl-amino]-2-methyl-pyridin-3-ylamino}-3-methoxy-pyridin-4- yloxy)-piperidine-1-carboxylic acidisopropyl ester 43

(S)-4-{6-[6-(2-Methanesulfonyl- propylamino)-2-methyl-pyridin-3-ylamino]-5-methoxy-pyrimidin-4- yloxy}-piperidine-1-carboxylic acidisopropyl ester 44

(R)-4-{6-[6-(2-Methanesulfonyl- propylamino)-2-methyl-pyridin-3-ylamino]-5-methoxy-pyrimidin-4- yloxy}-piperidine-1-carboxylic acidisopropyl ester 45

4-{2-[6-(3-Methanesulfonyl- pyrrolidin-1-yl)-2-methyl-pyridin-3-ylamino]-3-methoxy-pyridin-4- yloxy}-piperidine-1-carboxylic acidisopropyl ester 46

4-[2-(3-Methanesulfonyl-6′-methyl- 3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-ylamino)-3- methoxy-pyridin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester 47

4-[6-(6-Dimethylcarbamoylmethyl-2- methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]- piperidine-1-carboxylic acid isopropyl ester48

4-{2-[6-(3-Methanesulfonyl-azetidin-1-yl)-2-methyl-pyridin-3-ylamino]-3-methoxy-pyridin-4-yloxy}-piperidine- 1-carboxylic acid isopropyl ester49

4-[3-Ethynyloxy-2-(2-fluoro-4- methanesulfonyl-phenylamino)-pyridin-4-yloxy]-piperidine-1- carboxylic acid isopropyl ester 50

4-(6-{2-Fluoro-4-[(2-hydroxy- ethylcarbamoyl)-methyl]-phenylamino}-5-methoxy-pyrimidin- 3-yloxy)-piperidine-1-carboxylic acidisopropyl ester 51

4-{6-[6-(2-Methanesulfonyl- ethylamino)-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}- piperidine-1-carboxylic acid isopropyl ester52

4-{6-[2-Fluoro-4-(2-hydroxy- ethylsulfanyl)-phenylamino]-5-methoxy-pyrimidin-4-yloxy}- piperidine-1-carboxylic acid isopropyl ester53

4-{2-[2-Fluoro-4-(2-phosphonooxy- ethanesulfonyl)-phenylamino]-3-methoxy-pyridin-4-yloxy}-piperidine- 1-carboxylic acid isopropyl ester54

4-{6-[6-(2,3-Dihydroxy-propylamino)- 2-methyl-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}- piperidine-1-carboxylic acid isopropyl ester55

(S)-4-{6-[6-(2,3-Dihydroxy- propylamino)-2-methyl-pyridin-3-ylamino]-5-methoxy-pyrimidin-4- yloxy}-piperidine-1-carboxylic acidisopropyl ester 56

4-[2-(4-Ethanesulfonyl-2-fluoro- phenylamino)-3-methoxy-pyridin-4-yloxy]-piperidine-1-carboxylic acid sec-butyl ester 57

4-{2-[6-(2,3-Dihydroxy-propylamino)- 4-methyl-pyridin-3-ylamino]-3-methoxy-pyridin-4-yloxy}-piperidine- 1-carboxylic acid isopropyl ester58

4-{2-[6-(2-Hydroxy-ethylsulfanyl)- pyridin-3-ylamino]-3-methoxy-pyridin-4-yloxy}-piperidine-1- carboxylic acid isopropyl ester 59

4-{2-[2-Fluoro-4-(2-hydroxy- ethanesulfonyl)-phenylamino]-3-methoxy-pyridin-4-yloxy}-piperidine- 1-carboxylic acid isopropyl ester60

4-{2-[6-(2-Hydroxy-ethoxy)-2- methyl-pyridin-3-ylamino]-3-methoxy-pyridin-4-yloxy}-piperidine- 1-carboxylic acid isopropyl ester61

4-{6-[6-(2-Hydroxy-ethoxy)-2- methyl-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}- piperidine-1-carboxylic acid isopropyl ester62

4-{3-Methoxy-2-[2-methyl-6-(2- phosphonooxy-ethoxy)-pyridin-3-ylamino]-pyridin-4-yloxy}-piperidine- 1-carboxylic acid isopropyl ester63

4-{5-Methoxy-6-[2-methyl-6-(2- phosphonooxy-ethoxy)-pyridin-3-ylamino]-pyrimidin-4-yloxy}- piperidine-1-carboxylic acid isopropylester 64

4-{2-[6-(3-Hydroxy-propoxy)-2- methyl-pyridin-3-ylamino]-3-methoxy-pyridin-4-yloxy}-piperidine- 1-carboxylic acid isopropyl ester65

4-{6-[6-(3-Hydroxy-propoxy)-2- methyl-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}- piperidine-1-carboxylic acid isopropyl ester66

4-{3-Methoxy-2-[2-methyl-6-(3- phosphonooxy-propoxy)-pyridin-3-ylamino]-pyridin-4-yloxy}-piperidine- 1-carboxylic acid isopropyl ester67

4-{5-Methoxy-6-[2-methyl-6-(3- phosphonooxy-propoxy)-pyridin-3-ylamino]-pyrimidin-4-yloxy}- piperidine-1-carboxylic acid isopropylester 68

4-[3-Methoxy-2-(2-methoxy-4- sulfamoyl-phenylamino)-pyridin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester 69

4-{2-[2-Fluoro-4-(3-phosphonooxy- propyl)-phenylamino]-3-methoxy-pyridin-4-yloxy}-piperidine-1- carboxylic acid isopropyl ester 70

4-{2-[6-(2-Hydroxy-ethyl)-2-methyl- pyridin-3-ylamino]-3-methoxy-pyridin-4-yloxy}-piperidine-1- carboxylic acid isopropyl ester 71

4-{3-Methoxy-2-[2-methyl-6-(2- phosphonooxy-ethyl)-pyridin-3-ylamino]-pyridin-4-yloxy}-piperidine- 1-carboxylic acid isopropyl ester72

4-{2-[6-(3-Hydroxy-propyl)-2-methyl- pyridin-3-ylamino]-3-methoxy-pyridin-4-yloxy}-piperidine-1- carboxylic acid isopropyl ester 73

4-{3-Methoxy-2-[2-methyl-6-(3- phosphonooxy-propyl)-pyridin-3-ylamino]-pyridin-4-yloxy}-piperidine- 1-carboxylic acid isopropyl ester74

4-[6-(2,5-Difluoro-4-propoxy- phenylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester 75

4-[6-(4-Ethoxy-2,5-difluoro- phenylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester 76

4-[6-(2-Fluoro-4-methanesulfonyl- phenoxy)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester 77

4-[2-(2-Fluoro-4-methanesulfonyl- phenylamino)-3-methoxy-pyridin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester 78

4-{6-[6-(2-Hydroxy-ethylamino)-2- methyl-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}- piperidine-1-carboxylic acid isopropyl ester79

4-{6-[6-(2-Hydroxy-ethylsulfanyl)-2- methyl-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}- piperidine-1-carboxylic acid isopropyl ester80

4-{6-[6-(2-Hydroxy-ethylsulfanyl)- pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1- carboxylic acid isopropyl ester 81

4-{6-[6-(2-Methanesulfonyl- ethylamino)-2-methyl-pyridin-3-ylamino]-5-methoxy-pyrimidin-4- yloxy}-piperidine-1-carboxylic acidisopropyl ester 82

4-{2-[2-Fluoro-4-(2-methoxy-ethoxy)- phenylamino]-3-methoxy-pyridin-4-yloxy}-piperidine-1-carboxylic acid isopropyl ester 83

4-[6-(2,6-Dimethyl-pyridin-3- ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester 84

4-[6-(6-Methanesulfonyl-2-methyl- pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1- carboxylic acid isopropyl ester 85

4-[6-(6-Methanesulfonyl-4-methyl- pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1- carboxylic acid isopropyl ester 86

4-[5-Methoxy-6-(2-methyl-6- propylsulfanyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1- carboxylic acid isopropyl ester 87

4-{5-Methoxy-6-[2-methyl-6- (propane-1-sulfonyl)-pyridin-3-ylamino]-pyrimidin-4-yloxy}- piperidine-1-carboxylic acid isopropylester 88

4-[6-(6-Ethylsulfanyl-2-methyl- pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1- carboxylic acid isopropyl ester 89

4-[6-(6-Ethanesulfonyl-2-methyl- pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1- carboxylic acid isopropyl ester 90

4-[6-(6-Isopropylsulfanyl-2-methyl- pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1- carboxylic acid isopropyl ester 91

4-{5-Methoxy-6-[2-methyl-6- (propane-2-sulfonyl)-pyridin-3-ylamino]-pyrimidin-4-yloxy}- piperidine-1-carboxylic acid isopropylester 92

4-{6-[6-(2-Hydroxy-ethanesulfonyl)- 2-methyl-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}- piperidine-1-carboxylic acid isopropyl ester93

4-[5-Hydroxy-6-(6-methanesulfonyl- 2-methyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1- carboxylic acid isopropyl ester 94

4-[5-Ethoxy-6-(6-methanesulfonyl-2- methyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester 95

4-[5-Isopropoxy-6-(6- methanesulfonyl-2-methyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]- piperidine-1-carboxylic acid isopropylester 96

4-[6-(6-Methanesulfonyl-2-methyl- pyridin-3-ylamino)-5-propoxy-pyrimidin-4-yloxy]-piperidine-1- carboxylic acid isopropyl ester 97

4-[6-(6-Methanesulfonyl-2-methyl- pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1- carboxylic acid 1-ethyl-propyl ester 98

4-[6-(6-Methanesulfonyl-2-methyl- pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1- carboxylic acid sec-butyl ester 99

4-[6-(6-Cyano-4-methyl-pyridin-3- ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester 100

4-[6-(6-Hydroxymethyl-4-methyl- pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1- carboxylic acid isopropyl ester 101

{6-[1-(3-Isopropyl-[1,2,4]oxadiazol-5- yl)-piperidin-4-yloxy]-5-methoxy-pyrimidin-4-yl}-(6-methanesulfonyl- 2-methyl-pyridin-3-yl)-amine 102

4-[6-(6-Methanesulfonyl-2,4- dimethyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]- piperidine-1-carboxylic acid isopropyl ester103

4-{6-[6-(1-Methanesulfonyl-1-methyl-ethyl)-2-methyl-pyridin-3-ylamino]-5- methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylic acid isopropyl ester

Additionally, compounds of the present invention, including thoseillustrated in TABLE A, encompass all pharmaceutically acceptable salts,solvates, and particularly hydrates, thereof.

General Synthetic Methods

The de novo biosynthesis of pyrimidine nucleotides provides essentialprecursors for multiple growth-related events in higher eukaryotes.Assembled from ATP, bicarbonate and glutamine, the uracil and cytosinenucleotides are fuel for the synthesis of RNA, DNA, phospholipids, UDPsugars and glycogen. Over the past 2 decades considerable progress hasbeen made in elucidating the mechanisms by which cellular pyrimidinesare modulated to meet the needs of the cell. These studies point toincreasing evidence for cooperation between key cell signaling pathwaysand basic elements of cellular metabolism, and suggest that these eventshave the potential to determine distinct cellular fates, includinggrowth, differentiation and death.

As a result of their profound biological significance in highereukaryotes and utilization of the pyrimidine core in a number ofmarketed drugs (Scheme 1) and other medicinally relevant compounds,pyrimidines and pyridines play pivotal roles as chemotypes in drugdiscovery campaigns. As a direct consequence of this there is a wealthof scientific literature describing synthetic construction, as well aschemical modification and elaboration of these classes of heterocyles.

The novel substituted pyridine and pyrimidine derivatives of the currentinvention can prepared according to a variety of syntheticmanipulations, all of which would be familiar to one skilled in the artof synthetic organic chemistry. Certain methods for the preparation ofcompounds of the present invention include, but are not limited to,those described in Schemes 2-9 as set forth in this section of thespecification.

Common dichloro-substituted intermediate 8, used as a starting point forthe synthesis of compounds of the present invention can be prepared asdepicted in Scheme 2a. This is accomplished in two steps from adi-C₁₋₆-alkylmalonate, one particularly useful di-C₁₋₆-alkylmalonate isdiethyl malonate 5. Cyclization to the 4,6-dihydroxypyrimidine 7 isachieved by reacting 5 with formamidine in the presence of an alkalimetal alkoxide, by mixing the malonate and all or part of theformamidine with the alkoxide or with the alkoxide and the rest of theformamide. Alternative reagents such as dimethylmalonate, sodiummethoxide, formamide, in low molecular-weight alcoholic solvents,including methanol, ethanol, 2-propanol and the like, may be utilized inthe synthesis by heating at a temperature range between about 80 toabout 100° C. for about 30 mins to about 90 mins followed by a mineralacid work up. Preparation of dihydroxypyrimidines can also be achievedusing microorganisms such as Rhodococcus (see for reference WO97008152A1).

One intermediate used in the preparation of compounds of the presentinvention is Intermediate 8a. Chlorination of the 4 and 6 ring positionsto produce Intermediate 8a maybe carried out by reacting 7 with achlorinating reagent, such as, phosgene, POCl₃ (for reference see A.Gomtsyan et al., J. Med. Chem. 2002, 45, 3639-3648), thionyl chloride,oxalyl chloride and by mixtures of the above reagents includingPCl₃/POCl₃ at elevated reaction temperatures. The preparation ofIntermediate 8a is illustrated in Scheme 2a below:

Another intermediate that can be used in the preparation of compounds ofthe present invention is Intermediate 8b. The preparation ofIntermediate 8b can be prepared as illustrated in Scheme 2b. Nitrationof 2-chloro-3-hydroxy pyridine provides 2-chloro-4-nitro-pyridin-3-ol.The hydroxyl can be protected with a suitable group for use during theremaining steps of the scheme or the hydroxyl group can be alkylated,for example, methylated using TMS diazomethane to give2-chloro-3-methoxy-4-nitro-pyridine. Nucleophilic substitution of thenitro group with a 4-hydroxylpiperidine can provide Intermeidate 8b.Using similar steps, general Intermediate 8c can be prepared.

Conventional thermal aromatic substitution reactions of amines andalcohols with halogenated pyrimidines have been well documented (see forexample A. G. Arvanitis et al., J. Medicinal Chemistry, 1999, 42,805-818 and references therein). Nucleophilic aromatic (SN_(Ar))substitution reactions of electron deficient halogenated pyrimidines areusually rapid and high yielding. However, in certain cases, such aselectron rich or neutral halogenated heterocycles, successfulsubstitution is afforded by prolonged heating. To facilitate rapid entryinto many of the compounds of the invention microwave synthesis wasutilized (Schemes 3 and 4). The Smith synthesizer from PersonalChemistry is a commercially available focussed field heating instrumentthat provides safer and more uniform conditions for performing the basecatalysed substitution reactions depicted in Scheme. Bases employed forsuch conversions include tertiary amines such as triethylamine, Hunig'sbase (i.e. diisopropyl-ethylamine), N-methylmorpholine and the like.Alternatively, one skilled in the art can employ alkali metal hydrides,alkali metal carbonates (such as, Li₂CO₃, Na₂CO₃, K₂CO₃ and the like),an alkali metal hydrogencarbonate (such as, LiHCO₃, NaHCO₃, KHCO₃ andthe like). Suitable solvents include ethereal solvent such astetrahydrofuran, 1,4-dioxane, and the like. Reaction times to accesstypical intermediates, such as Intermediate 10, can range from about 300s to about 3000 s and when conventional thermal methods are employedabout 20 mins to about 120 mins.

Methods for conversion of intermediate monosubstituted pyridine andpyrimidine 10 are illustrated in Scheme 4. One method includes usingpalladium catalysed aminations. This synthetic strategy has emerged as apowerful tool for synthesis of substituted aryl and heteroaryl anilinesin recent times (for reference see S. L. Buchwald., Top. Curr. Chem.,2002, 219, 131 and references therein). Addition reactions can beconducted using a suitably substituted amine (Intermediate 16) oralcohol (Intermediate 17) in the presence of a palladium or alternative

transition metal catalyst selected from, but not limited to, Pd₂(dba)₃,Pd(OAc)₂, CuI, Cu(OTf)₂, Ni(COD)₂, Ni(acac)₂ in a suitable anhydroussolvent (such as, THF, 1,4-dioxane, and the like) with as strong alkalimetal alkoxide base (such as, NaO^(t)Bu, KO^(t)Bu and the like). Asuitable ligand employed in this step can be selected from BINAP,P(o-tolyl)₃, tBu₃P, DPPF, P[N(^(i)Bu)CH₂CH₃]₃N and the like when thecatalyst is a palladium derived complex.

Alternatively, for “Ullman-type” aryl aminations catalyzed by copperderived complexes, the base employed may be selected from an alkalimetal carbonate in an aprotic polar solvent (such asN,N-dimethylacetamide, DMF, DMSO, and the like) with L-proline,N-methylglycine or diethylsalicyclamide as the ligand (for reference seeD. Ma, Organic Lett., 2003, 5, 14, 2453-2455).

Compounds of general Formulae 12 to 15 may also be obtained by reversingthe order of the reaction steps (i.e. introduction of Nuc 2 followed byNuc 1), wherein the initial step comprises of introduction of eitherIntermediate 16 or 17 by using base in ^(i)PrOH followed by addition of4N HCl in dioxane followed by addition of the substituted4-hydroxylpiperdinyl.

As illustrated in Scheme 5, a similar transition metal catalyzedcouplings can also be utilized to obtain molecules of general Formula21a (Scheme 5a) wherein the Intermediate 20 (Hal=Br, I and the like) ismodified to give analogs with alkyl amino substituents (i.e.,NR_(a)R_(b), wherein R_(a) and R_(b) are each independently H, C₁₋₆alkyl or a C₁₋₆ alkyl optionally substituted as described herein, orR_(a) and R_(b) together with the nitrogen form a heterocyclic ring,such as pyrrolidine, piperdine, and the like). Alternatively, the linkeratom can be oxygen by utilizing the CuI catalyzed method for aromaticC—O formation described by Buchwald (see for reference S. L. Buchwald;Organic Lett., 2002, 4, 6, 973-976) by utilizing, for example, 10 mol %CuI, 20 mol % 1,10-phenanthroline, 2 equivalents of Cs₂CO₃, at 110° C.for 18 h, with an iodo substitution in Intermediate 20 (Scheme 5b).

Alternatively, compounds of Formulae 21a and 21b can also be prepared asillustrated in Scheme 5c.

This method is particularly useful for when R₃ is an alkoxy group. Avariety of alcohol, amine and thiol compounds can be introducedresulting in the R₅ group to provide Intermediates 21c, 21d and 21e.Intermediates 21c, 21d and 21e can subsequently be reduced to thecorresponding amines and finally coupled to provide compounds of thepresent invention. Coupling methods include those described in Scheme 4ato 4d, supra.

A particular substitution for Intermediates 12, 13, 14, and 15 iswherein R₁═C(O)O—C₁₋₆ alkyl wherein the alkyl is optionally substitutedas described herein. Urethanes of this type can be prepared directlyfrom intermediates depicted in Schemes 3 and 4 when R₁═H. In certainreactions, use of a suitable nitrogen protecting group (such as,^(t)Boc, Cbz, Moz, Alloc, Fmoc and the like) may be necessary duringfurther chemical modification of the core. Deprotection can be achievedusing standard reagents familiar to one skilled in the art (these mightinclude TFA, mineral acid, Palladium/hydrogen gas and the like in analcoholic or ethereal solvent system chosen from methanol, ethanol,tert-butanol, THF, 1,4-dioxane, and the like). On occasion wherein thetarget molecule contains 2 protecting groups, an orthogonal protectionstrategy may be adopted. The deprotected secondary amine (R₁ ═H) cansubsequently be modified accordingly.

Schemes 6 and 7 illustrate such chemistries wherein generation of acarbamate can be executed using an appropriate reaction in the presenceof a base, for example, a tertiary amine base such as TEA, DIEA and thelike, in an inert solvent system.

As illustrated in Scheme 6, Urethane 23 can be obtained by a urethanereaction using R_(c)OC(O)-halide (wherein R_(c) is C₁₋₆ alkyl optionallysubstituted as described herein, and halide is chloro, bromo, or iodo,particularly useful is chloro) in an inert solvent with or without abase. Suitable bases include an alkali metal carbonate (such as, sodiumcarbonate, potassium carbonate, and the like), an alkali metalhydrogencarbonate (such as, sodium hydrogencarbonate, potassiumhydrogencarbonate, and the like), an alkali hydroxide (such as, sodiumhydroxide, potassium hydroxide, and the like), a tertiary amine (suchas, N,N-diisopropylethylamine, triethylamine, N-methylmorpholine, andthe like), or an aromatic amine (such as, pyridine, imidazole,poly-(4-vinylpyridine), and the like).

The inert solvent includes lower halocarbon solvents (such as,dichloromethane, dichloroethane, chloroform, and the like), etherealsolvents (such as, tetrahydrofuran, dioxane, and the like), aromaticsolvents (such as, benzene, toluene, and the like), or polar solvents(such as, N,N-dimethylformamide, dimethyl sulfoxide, and the like).Reaction temperature ranges from about −20° C. to 120° C., preferablyabout 0° C. to 100° C.

Scheme 7 illustrates the synthesis of aryl/hetero-alkyl sulfones 26which are used as aryl building blocks in Scheme 4 of the presentinvention. The common methods for preparing these sulfones include theoxidation of sulfides using an oxidizing agent (i.e., H₂O₂) or thesulfonylation of arenes using aryl sulfonyl halides or aryl sulfonicacids in the presence of a strong acid catalyst (see for generalreference: the Organic Chemistry of Sulfur; Oae S., Ed.; Plenum Press:New York, 1977). Optimal conversion to the optionally 2,5-disubstitutedarene 26 was achieved thermally wherein Hal is preferably iodo using 5mol % (CuOTf)₂.PhH and 10 mol % N,N′-dimethylethylenediamine in DMSO bythe method of Wang et al (see for reference Wang Z.; Baskin J. M., Org.Lett., 2002, 4, 25, 4423-4425). In some embodiments, R₄ and R₆ are eachindependently H, halogen, or C₁₋₆ alkyl; R₇ is H; Hal=Br, I; and Y═O orNH.

Alternative standard organic synthetic methods may be used to introducealternate substituents in to the Ar component. In one example whereinthe linker atom is Y═NH, the manipulation maybe carried out byprotecting the aniline amino functionality using standard FmocCl andCbzCl protection deprotection steps familiar to one skilled in the art(Scheme 8, wherein R₄, R₆ and R₇ have the same meaning as describedherein) and subsequently using the deprotected aniline in subsequentsteps such as those depicted in Scheme 4. In some embodiments of theinvention R₄ is halogen, and R₆ is H or halogen.

Synthesis of the 3,5-oxadiazolyl variant is depicted in Scheme 9.Zinc(II)chloride catalysed coupling of amidoxime 34 with4-hydroxypiperidine, CNBr derived 36 yielded building block 37 afteracidic workup, which was subsequently utilized in reaction sequencesdepicted as illustrated in Scheme 3.

Protecting groups may be required for various functionality orfunctionalities during the synthesis of some of the compounds of theinvention. Accordingly, representative protecting groups that aresuitable for a wide variety of synthetic transformations are disclosedin Greene and Wuts, Protective Groups in Organic Synthesis, 3rd edition,John Wiley & Sons, New York, 1999, the disclosure of which isincorporated herein by reference in its entirety.

The present invention also encompasses diastereomers as well as opticalisomers, e.g. mixtures of enantiomers including racemic mixtures, aswell as individual enantiomers and diastereomers, which arise as aconsequence of structural asymmetry in certain compounds of the presentinvention. Separation of the individual isomers or selective synthesisof the individual isomers is accomplished by application of variousmethods which are well known to practitioners in the art.

Indications and Methods of Treatment

In addition to the foregoing beneficial uses for compounds of thepresent invention disclosed herein, compounds of the invention areuseful in the treatment of additional diseases. Without limitation,these include the following.

The most significant pathologies in Type II diabetes are impairedinsulin signaling at its target tissues (“insulin resistance”) andfailure of the insulin-producing cells of the pancreas to secrete anappropriate degree of insulin in response to a hyperglycemic signal.Current therapies to treat the latter include inhibitors of the β-cellATP-sensitive potassium channel to trigger the release of endogenousinsulin stores, or administration of exogenous insulin. Neither of theseachieves accurate normalization of blood glucose levels and both carrythe risk of inducing hypoglycemia. For these reasons, there has beenintense interest in the development of pharmaceuticals that function ina glucose-dependent action, i.e. potentiators of glucose signaling.Physiological signaling systems which function in this manner arewell-characterized and include the gut peptides GLP1, GIP and PACAP.These hormones act via their cognate G-protein coupled receptor tostimulate the production of cAMP in pancreatic β-cells. The increasedcAMP does not appear to result in stimulation of insulin release duringthe fasting or preprandial state. However, a series of biochemicaltargets of cAMP signaling, including the ATP-sensitive potassiumchannel, voltage-sensitive potassium channels and the exocytoticmachinery, are modified in such a way that the insulin secretoryresponse to a postprandial glucose stimulus is markedly enhanced.Accordingly, agonists of novel, similarly functioning, β-cell GPCRs,including RUP3, would also stimulate the release of endogenous insulinand consequently promote normoglycemia in Type II diabetes.

It is also established that increased cAMP, for example as a result ofGLP1 stimulation, promotes β-cell proliferation, inhibits β-cell deathand thus improves islet mass. This positive effect on β-cell mass isexpected to be beneficial in both Type II diabetes, where insufficientinsulin is produced, and Type I diabetes, where β-cells are destroyed byan inappropriate autoimmune response.

Some β-cell GPCRs, including RUP3, are also present in the hypothalamuswhere they modulate hunger, satiety, decrease food intake, controllingor decreasing weight and energy expenditure. Hence, given their functionwithin the hypothalamic circuitry, agonists or inverse agonists of thesereceptors mitigate hunger, promote satiety and therefore modulateweight.

It is also well-established that metabolic diseases exert a negativeinfluence on other physiological systems. Thus, there is often thecodevelopment of multiple disease states (e.g. type I diabetes, type IIdiabetes, inadequate glucose tolerance, insulin resistance,hyperglycemia, hyperlipidemia, hypertriglyceridemia,hypercholesterolemia, dyslipidemia, obesity or cardiovascular disease in“Syndrome X”) or secondary diseases which clearly occur secondary todiabetes (e.g. kidney disease, peripheral neuropathy). Thus, it isexpected that effective treatment of the diabetic condition will in turnbe of benefit to such interconnected disease states.

In some embodiments of the present invention the metabolic-relateddisorder is hyperlipidemia, type 1 diabetes, type 2 diabetes mellitus,idiopathic type 1 diabetes (Type 1b), latent autoimmune diabetes inadults (LADA), early-onset type 2 diabetes (EOD), youth-onset atypicaldiabetes (YOAD), maturity onset diabetes of the young (MODY),malnutrition-related diabetes, gestational diabetes, coronary heartdisease, ischemic stroke, restenosis after angioplasty, peripheralvascular disease, intermittent claudication, myocardial infarction (e.g.necrosis and apoptosis), dyslipidemia, post-prandial lipemia, conditionsof impaired glucose tolerance (IGT), conditions of impaired fastingplasma glucose, metabolic acidosis, ketosis, arthritis, obesity,osteoporosis, hypertension, congestive heart failure, left ventricularhypertrophy, peripheral arterial disease, diabetic retinopathy, maculardegeneration, cataract, diabetic nephropathy, glomerulosclerosis,chronic renal failure, diabetic neuropathy, metabolic syndrome, syndromeX, premenstrual syndrome, coronary heart disease, angina pectoris,thrombosis, atherosclerosis, myocardial infarction, transient ischemicattacks, stroke, vascular restenosis, hyperglycemia, hyperinsulinemia,hyperlipidemia, hypertrygliceridemia, insulin resistance, impairedglucose metabolism, conditions of impaired glucose tolerance, conditionsof impaired fasting plasma glucose, obesity, erectile dysfunction, skinand connective tissue disorders, foot ulcerations and ulcerativecolitis, endothelial dysfunction and impaired vascular compliance.

One aspect of the present invention pertains to methods for treatment ofa metabolic-related disorder in an individual comprising administeringto the individual in need of such treatment a therapeutically effectiveamount of a compound as described herein or a pharmaceutical compositionthereof. In some embodiments the metabolic-related disorder is type Idiabetes, type II diabetes, inadequate glucose tolerance, insulinresistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia,hypercholesterolemia, dyslipidemia or syndrome X. In some embodimentsthe metabolic-related disorder is type II diabetes. In some embodimentsthe metabolic-related disorder is hyperglycemia. In some embodiments themetabolic-related disorder is hyperlipidemia. In some embodiments themetabolic-related disorder is hypertriglyceridemia. In some embodimentsthe metabolic-related disorder is type I diabetes. In some embodimentsthe metabolic-related disorder is dyslipidemia. In some embodiments themetabolic-related disorder is syndrome X. In some embodiments theindividual is a mammal. In some embodiments the mammal is a human.

One aspect of the present invention pertains to methods of decreasingfood intake of an individual comprising administering to the individualin need thereof a therapeutically effective amount of a compound of thepresent invention or pharmaceutical composition thereof. In someembodiments the individual is a mammal. In some embodiments the mammalis a human.

One aspect of the present invention pertains to methods of inducingsatiety in an individual comprising administering to the individual inneed of such treatment a therapeutically effective amount of a compoundof the present invention or pharmaceutical composition thereof. In someembodiments the individual is a mammal. In some embodiments the mammalis a human.

One aspect of the present invention pertains to methods of controllingor decreasing weight gain of an individual comprising administering tothe individual in need of such treatment a therapeutically effectiveamount of a compound of the present invention or pharmaceuticalcomposition thereof. In some embodiments the individual is a mammal. Insome embodiments the mammal is a human.

Some embodiments of the present invention pertain to methods wherein thehuman has a body mass index of about 18.5 to about 45. In someembodiments, the human has a body mass index of about 25 to about 45. Insome embodiments, the human has a body mass index of about 30 to about45. In some embodiments, the human has a body mass index of about 35 toabout 45.

One aspect of the present invention pertains to methods of modulating aRUP3 receptor in an individual comprising contacting the receptor with acompound according to any one of claims 1 to 127. In some embodiments,the compound is an agonist. In some embodiments, the compound is aninverse agonist. In some embodiments, the compound is an antagonist. Insome embodiments, the modulation of the RUP3 receptor is treatment of ametabolic-related disorder and complications thereof. In someembodiments, the metabolic-related disorder is type I diabetes, type IIdiabetes, inadequate glucose tolerance, insulin resistance,hyperglycemia, hyperlipidemia, hypertriglyceridemia,hypercholesterolemia, dyslipidemia or syndrome X. In some embodiments,the metabolic-related disorder is type II diabetes. In some embodiments,the metabolic-related disorder is hyperglycemia. In some embodiments,the metabolic-related disorder is hyperlipidemia. In some embodiments,the metabolic-related disorder is hypertriglyceridemia. In someembodiments, the metabolic-related disorder is type I diabetes. In someembodiments, the metabolic-related disorder is dyslipidemia. In someembodiments, the metabolic-related disorder is syndrome X. In someembodiments, the individual is a mammal. In some embodiments, the mammalis a human.

Some embodiments of the present invention include a method of modulatinga RUP3 receptor in an individual comprising contacting the receptor witha compound of the present invention wherein the modulation of the RUP3receptor reduces food intake of the individual. In some embodiments theindividual is a mammal. In some embodiments the mammal is a human. Insome embodiments the human has a body mass index of about 18.5 to about45. In some embodiments the human has a body mass index of about 25 toabout 45. In some embodiments the human has a body mass index of about30 to about 45. In some embodiments the human has a body mass index ofabout 35 to about 45.

Some embodiments of the present invention include a method of modulatinga RUP3 receptor in an individual comprising contacting the receptor witha compound of the present invention wherein the modulation of the RUP3receptor induces satiety in the individual. In some embodiments theindividual is a mammal. In some embodiments the mammal is a human. Insome embodiments the human has a body mass index of about 18.5 to about45. In some embodiments the human has a body mass index of about 25 toabout 45. In some embodiments the human has a body mass index of about30 to about 45. In some embodiments the human has a body mass index ofabout 35 to about 45.

Some embodiments of the present invention include a method of modulatinga RUP3 receptor in an individual comprising contacting the receptor witha compound of the present invention wherein the modulation of the RUP3receptor controls or reduces weight gain of the individual. In someembodiments the individual is a mammal. In some embodiments the mammalis a human. In some embodiments the human has a body mass index of about18.5 to about 45. In some embodiments the human has a body mass index ofabout 25 to about 45. In some embodiments the human has a body massindex of about 30 to about 45. In some embodiments the human has a bodymass index of about 35 to about 45.

One aspect of the present invention pertains to use of a compound asdescribed herein, for production of a medicament for use in treatment ofa metabolic-related disorder. In some embodiments, the metabolic-relateddisorder is type II diabetes, inadequate glucose tolerance, insulinresistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia,hypercholesterolemia, dyslipidemia or syndrome X.

One aspect of the present invention pertains to use of a compound asdescribed herein, for production of a medicament for use in decreasingfood intake of an individual. In some embodiments, the individual is amammal. In some embodiments, the mammal is a human. In some embodiments,the human has a body mass index of about 18.5 to about 45. In someembodiments, the human has a body mass index of about 25 to about 45. Insome embodiments, the human has a body mass index of about 30 to about45. In some embodiments, the human has a body mass index of about 35 toabout 45.

One aspect of the present invention pertains to use of a compound asdescribed herein, for production of a medicament for use of inducingsatiety in an individual. In some embodiments, the individual is amammal. In some embodiments, the mammal is a human. In some embodiments,the human has a body mass index of about 18.5 to about 45. In someembodiments, the human has a body mass index of about 25 to about 45. Insome embodiments, the human has a body mass index of about 30 to about45. In some embodiments, the human has a body mass index of about 35 toabout 45.

One aspect of the present invention pertains to use of a compound asdescribed herein, for production of a medicament for use in controllingor decreasing weight gain in an individual. In some embodiments, theindividual is a mammal. In some embodiments, the mammal is a human. Insome embodiments, the human has a body mass index of about 18.5 to about45. In some embodiments, the human has a body mass index of about 25 toabout 45. In some embodiments, the human has a body mass index of about30 to about 45. In some embodiments, the human has a body mass index ofabout 35 to about 45.

One aspect of the present invention pertains to a compound, as describedherein, for use in a method of treatment of the human or animal body bytherapy.

One aspect of the present invention pertains to a compound, as describedherein, for use in a method of treatment of a metabolic-related disorderof the human or animal body by therapy.

Pharmaceutical Compositions and Salts

A further aspect of the present invention pertains to pharmaceuticalcompositions comprising one or more compounds of Formula (Ia) or anyformula disclosed herein, and one or more pharmaceutically acceptablecarriers. Some embodiments of the present invention pertain topharmaceutical compositions comprising a compound of Formula (Ia) and apharmaceutically acceptable carrier.

Some embodiments of the present invention include a method of producinga pharmaceutical composition comprising admixing at least one compoundaccording to any of the compound embodiments disclosed herein and apharmaceutically acceptable carrier.

Formulations may be prepared by any suitable method, typically byuniformly mixing the active compound(s) with liquids or finely dividedsolid carriers, or both, in the required proportions, and then, ifnecessary, forming the resulting mixture into a desired shape.

Conventional excipients, such as binding agents, fillers, acceptablewetting agents, tabletting lubricants, and disintegrants may be used intablets and capsules for oral administration. Liquid preparations fororal administration may be in the form of solutions, emulsions, aqueousor oily suspensions, and syrups. Alternatively, the oral preparationsmay be in the form of dry powder that can be reconstituted with water oranother suitable liquid vehicle before use. Additional additives such assuspending or emulsifying agents, non-aqueous vehicles (including edibleoils), preservatives, and flavorings and colorants may be added to theliquid preparations. Parenteral dosage forms may be prepared bydissolving the compound of the invention in a suitable liquid vehicleand filter sterilizing the solution before filling and sealing anappropriate vial or ampoule. These are just a few examples of the manyappropriate methods well known in the art for preparing dosage forms.

A compound of the present invention can be formulated intopharmaceutical compositions using techniques well known to those in theart. Suitable pharmaceutically-acceptable carriers, outside thosementioned herein, are known in the art; for example, see Remington, TheScience and Practice of Pharmacy, 20th Edition, 2000, LippincottWilliams & Wilkins, (Editors: Gennaro, A. R., et al.).

While it is possible that, for use in the treatment, a compound of theinvention may, in an alternative use, be administered as a raw or purechemical, it is preferable however to present the compound or activeingredient as a pharmaceutical formulation or composition furthercomprising a pharmaceutically acceptable carrier.

The invention thus further provides pharmaceutical formulationscomprising a compound of the invention or a pharmaceutically acceptablesalt or derivative thereof together with one or more pharmaceuticallyacceptable carriers thereof and/or prophylactic ingredients. Thecarrier(s) must be “acceptable” in the sense of being compatible withthe other ingredients of the formulation and not overly deleterious tothe recipient thereof.

Pharmaceutical formulations include those suitable for oral, rectal,nasal, topical (including buccal and sub-lingual), vaginal or parenteral(including intramuscular, sub-cutaneous and intravenous) administrationor in a form suitable for administration by inhalation, insufflation orby a transdermal patch. Transdermal patches dispense a drug at acontrolled rate by presenting the drug for absorption in an efficientmanner with a minimum of degradation of the drug. Typically, transdermalpatches comprise an impermeable backing layer, a single pressuresensitive adhesive and a removable protective layer with a releaseliner. One of ordinary skill in the art will understand and appreciatethe techniques appropriate for manufacturing a desired efficacioustransdermal patch based upon the needs of the artisan.

The compounds of the invention, together with a conventional adjuvant,carrier, or diluent, may thus be placed into the form of pharmaceuticalformulations and unit dosages thereof, and in such form may be employedas solids, such as tablets or filled capsules, or liquids such assolutions, suspensions, emulsions, elixirs, gels or capsules filled withthe same, all for oral use, in the form of suppositories for rectaladministration; or in the form of sterile injectable solutions forparenteral (including subcutaneous) use. Such pharmaceuticalcompositions and unit dosage forms thereof may comprise conventionalingredients in conventional proportions, with or without additionalactive compounds or principles, and such unit dosage forms may containany suitable effective amount of the active ingredient commensurate withthe intended daily dosage range to be employed.

For oral administration, the pharmaceutical composition may be in theform of, for example, a tablet, capsule, suspension or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a particular amount of the active ingredient. Examplesof such dosage units are capsules, tablets, powders, granules or asuspension, with conventional additives such as lactose, mannitol, cornstarch or potato starch; with binders such as crystalline cellulose,cellulose derivatives, acacia, corn starch or gelatins; withdisintegrators such as corn starch, potato starch or sodiumcarboxymethyl-cellulose; and with lubricants such as talc or magnesiumstearate. The active ingredient may also be administered by injection asa composition wherein, for example, saline, dextrose or water may beused as a suitable pharmaceutically acceptable carrier.

Compounds of the present invention, including pharmaceuticallyacceptable salts and solvates thereof, can be used as active ingredientsin pharmaceutical compositions, specifically as RUP3 receptormodulators. By the term “active ingredient” is defined in the context ofa “pharmaceutical composition” and shall mean a component of apharmaceutical composition that provides the primary pharmacologicaleffect, as opposed to an “inactive ingredient” which would generally berecognized as providing no pharmaceutical benefit.

The dose when using the compounds of the present invention can varywithin wide limits, and as is customary and is known to the physician,it is to be tailored to the individual conditions in each individualcase. It depends, for example, on the nature and severity of the illnessto be treated, on the condition of the patient, on the compound employedor on whether an acute or chronic disease state is treated orprophylaxis is conducted or on whether further active compounds areadministered in addition to the compounds of the present invention.Representative doses of the present invention include, but not limitedto, about 0.001 mg to about 5000 mg, about 0.001 to about 2500 mg, about0.001 to about 1000 mg, 0.001 to about 500 mg, 0.001 mg to about 250 mg,about 0.001 mg to 100 mg, about 0.001 mg to about 50 mg, and about 0.001mg to about 25 mg. Multiple doses may be administered during the day,especially when relatively large amounts are deemed to be needed, forexample 2, 3 or 4, doses. Depending on the individual and as deemedappropriate from the patient's physician or care-giver it may benecessary to deviate upward or downward from the doses described herein.

The amount of active ingredient, or an active salt or derivativethereof, required for use in treatment will vary not only with theparticular salt selected but also with the route of administration, thenature of the condition being treated and the age and condition of thepatient and will ultimately be at the discretion of the attendantphysician or clinician. In general, one skilled in the art understandshow to extrapolate in vivo data obtained in a model system, typically ananimal model, to another, such as a human. Typically, animal modelsinclude, but are not limited to, the rodent diabetes model as describedin Example 5, infra (as well as other animal models known in the art,such as those reported by Reed and Scribner in Diabetes, Obesity andMetabolism, 1, 1999, 75-86). In some circumstances, these extrapolationsmay merely be based on the weight of the animal in the respective modelin comparison to another, such as a mammal, preferably a human, however,more often, these extrapolations are not simply based on weights, butrather incorporate a variety of factors. Representative factors include,but not limited to, the type, age, weight, sex, diet and medicalcondition of the patient, the severity of the disease, the route ofadministration, pharmacological considerations such as the activity,efficacy, pharmacokinetic and toxicology profiles of the particularcompound employed, whether a drug delivery system is utilized, onwhether an acute or chronic disease state is being treated orprophylaxis is conducted or on whether further active compounds areadministered in addition to the compounds of the present invention andas part of a drug combination. The dosage regimen for treating a diseasecondition with the compounds and/or compositions of this invention isselected in accordance with a variety factors as cited above. Thus, theactual dosage regimen employed may vary widely and therefore may deviatefrom a preferred dosage regimen and one skilled in the art willrecognize that dosage and dosage regimen outside these typical rangescan be tested and, where appropriate, may be used in the methods of thisinvention.

The desired dose may conveniently be presented in a single dose or asdivided doses administered at appropriate intervals, for example, astwo, three, four or more sub-doses per day. The sub-dose itself may befurther divided, e.g., into a number of discrete loosely spacedadministrations. The daily dose can be divided, especially whenrelatively large amounts are administered as deemed appropriate, intoseveral, for example 2, 3 or 4, part administrations. If appropriate,depending on individual behavior, it may be necessary to deviate upwardor downward from the daily dose indicated.

The compounds of the present invention can be administrated in a widevariety of oral and parenteral dosage forms. It will be obvious to thoseskilled in the art that the following dosage forms may comprise, as theactive component, either a compound of the invention or apharmaceutically acceptable salt of a compound of the invention.

For preparing pharmaceutical compositions from the compounds of thepresent invention, the selection of a suitable pharmaceuticallyacceptable carrier can be either solid, liquid or a mixture of both.Solid form preparations include powders, tablets, pills, capsules,cachets, suppositories, and dispersible granules. A solid carrier can beone or more substances which may also act as diluents, flavouringagents, solubilizers, lubricants, suspending agents, binders,preservatives, tablet disintegrating agents, or an encapsulatingmaterial.

In powders, the carrier is a finely divided solid which is in a mixturewith the finely divided active component.

In tablets, the active component is mixed with the carrier having thenecessary binding capacity in suitable proportions and compacted to thedesire shape and size.

The powders and tablets may contain varying percentage amounts of theactive compound. A representative amount in a powder or tablet maycontain from 0.5 to about 90 percent of the active compound; however, anartisan would know when amounts outside of this range are necessary.Suitable carriers for powders and tablets are magnesium carbonate,magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch,gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, alow melting wax, cocoa butter, and the like. The term “preparation” isintended to include the formulation of the active compound withencapsulating material as carrier providing a capsule in which theactive component, with or without carriers, is surrounded by a carrier,which is thus in association with it. Similarly, cachets and lozengesare included. Tablets, powders, capsules, pills, cachets, and lozengescan be used as solid forms suitable for oral administration.

For preparing suppositories, a low melting wax, such as an admixture offatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogenous mixture is then poured into convenient sized molds, allowedto cool, and thereby to solidify.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or sprays containing inaddition to the active ingredient such carriers as are known in the artto be appropriate.

Liquid form preparations include solutions, suspensions, and emulsions,for example, water or water-propylene glycol solutions. For example,parenteral injection liquid preparations can be formulated as solutionsin aqueous polyethylene glycol solution. Injectable preparations, forexample, sterile injectable aqueous or oleaginous suspensions may beformulated according to the known art using suitable dispersing orwetting agents and suspending agents. The sterile injectable preparationmay also be a sterile injectable solution or suspension in a nontoxicparenterally acceptable diluent or solvent, for example, as a solutionin 1,3-butanediol. Among the acceptable vehicles and solvents that maybe employed are water, Ringer's solution, and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose any bland fixed oilmay be employed including synthetic mono- or diglycerides. In addition,fatty acids such as oleic acid find use in the preparation ofinjectables.

The compounds according to the present invention may thus be formulatedfor parenteral administration (e.g. by injection, for example bolusinjection or continuous infusion) and may be presented in unit dose formin ampoules, pre-filled syringes, small volume infusion or in multi-dosecontainers with an added preservative. The pharmaceutical compositionsmay take such forms as suspensions, solutions, or emulsions in oily oraqueous vehicles, and may contain formulatory agents such as suspending,stabilizing and/or dispersing agents. Alternatively, the activeingredient may be in powder form, obtained by aseptic isolation ofsterile solid or by lyophilization from solution, for constitution witha suitable vehicle, e.g. sterile, pyrogen-free water, before use.

Aqueous formulations suitable for oral use can be prepared by dissolvingor suspending the active component in water and adding suitablecolorants, flavours, stabilizing and thickening agents, as desired.

Aqueous suspensions suitable for oral use can be made by dispersing thefinely divided active component in water with viscous material, such asnatural or synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, or other well known suspending agents.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

For topical administration to the epidermis the compounds according tothe invention may be formulated as ointments, creams or lotions, or as atransdermal patch.

Ointments and creams may, for example, be formulated with an aqueous oroily base with the addition of suitable thickening and/or gellingagents. Lotions may be formulated with an aqueous or oily base and willin general also contain one or more emulsifying agents, stabilizingagents, dispersing agents, suspending agents, thickening agents, orcoloring agents.

Formulations suitable for topical administration in the mouth includelozenges comprising active agent in a flavored base, usually sucrose andacacia or tragacanth; pastilles comprising the active ingredient in aninert base such as gelatin and glycerin or sucrose and acacia; andmouthwashes comprising the active ingredient in a suitable liquidcarrier.

Solutions or suspensions are applied directly to the nasal cavity byconventional means, for example with a dropper, pipette or spray. Theformulations may be provided in single or multi-dose form. In the lattercase of a dropper or pipette, this may be achieved by the patientadministering an appropriate, predetermined volume of the solution orsuspension. In the case of a spray, this may be achieved for example bymeans of a metering atomizing spray pump.

Administration to the respiratory tract may also be achieved by means ofan aerosol formulation in which the active ingredient is provided in apressurized pack with a suitable propellant. If the compounds of thepresent invention or pharmaceutical compositions comprising them areadministered as aerosols, for example as nasal aerosols or byinhalation, this can be carried out, for example, using a spray, anebulizer, a pump nebulizer, an inhalation apparatus, a metered inhaleror a dry powder inhaler. Pharmaceutical forms for administration of thecompounds of the present invention as an aerosol can be prepared byprocesses well-known to the person skilled in the art. For theirpreparation, for example, solutions or dispersions of the compounds ofthe present invention in water, water/alcohol mixtures or suitablesaline solutions can be employed using customary additives, for examplebenzyl alcohol or other suitable preservatives, absorption enhancers forincreasing the bioavailability, solubilizers, dispersants and others,and, if appropriate, customary propellants, for example include carbondioxide, CFC's, such as, dichlorodifluoromethane,trichlorofluoromethane, or dichlorotetrafluoroethane; and the like. Theaerosol may conveniently also contain a surfactant such as lecithin. Thedose of drug may be controlled by provision of a metered valve.

In formulations intended for administration to the respiratory tract,including intranasal formulations, the compound will generally have asmall particle size for example of the order of 10 microns or less. Sucha particle size may be obtained by means known in the art, for exampleby micronization. When desired, formulations adapted to give sustainedrelease of the active ingredient may be employed.

Alternatively the active ingredients may be provided in the form of adry powder, for example, a powder mix of the compound in a suitablepowder base such as lactose, starch, starch derivatives such ashydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).Conveniently the powder carrier will form a gel in the nasal cavity. Thepowder composition may be presented in unit dose form for example incapsules or cartridges of, e.g., gelatin, or blister packs from whichthe powder may be administered by means of an inhaler.

The pharmaceutical preparations are preferably in unit dosage forms. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

Tablets or capsules for oral administration and liquids for intravenousadministration are preferred compositions.

The compounds according to the invention may optionally exist aspharmaceutically acceptable salts including pharmaceutically acceptableacid addition salts prepared from pharmaceutically acceptable non-toxicacids including inorganic and organic acids. Representative acidsinclude, but are not limited to, acetic, benzenesulfonic, benzoic,camphorsulfonic, citric, ethenesulfonic, dichloroacetic, formic,fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric,isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic,nitric, oxalic, pamoic, pantothenic, phosphoric, succinic, sulfiric,tartaric, oxalic, p-toluenesulfonic and the like, such as thosepharmaceutically acceptable salts listed in Journal of PharmaceuticalScience, 66, 2 (1977); incorporated herein by reference in its entirety.

The acid addition salts may be obtained as the direct product ofcompound synthesis. In the alternative, the free base may be dissolvedin a suitable solvent containing the appropriate acid, and the saltisolated by evaporating the solvent or otherwise separating the salt andsolvent. The compounds of this invention may form solvates with standardlow molecular weight solvents using methods known to the skilledartisan.

In addition, compounds according to the invention may optionally existas pharmaceutically acceptable basic addition salts. For example, thesesalts can be prepared in situ during the final isolation andpurification of the compounds of the invention, or separately byreacting an acidic moiety, such as a carboxylic acid, with a suitablebase such as the hydroxide, carbonate or bicarbonate of apharmaceutically acceptable metal cation or with ammonia, or an organicprimary, secondary or tertiary amine. Pharmaceutically acceptable saltsinclude, but are not limited to, cations based on the alkali andalkaline earth metals, such as sodium, lithium, potassium, calcium,magnesium, aluminum salts and the like, as well as nontoxic ammonium,quaternary ammonium, and amine cations, including, but not limited toammonium, tetramethylammonium, tetraethylammonium, methylamine,dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.Other representative organic amines useful for the formation of baseaddition salts include diethylamine, ethylenediamine, ethanolamine,diethanolamine, piperazine and the like.

Compounds of the present invention can be converted to “pro-drugs.” Theterm “pro-drugs” refers to compounds that have been modified withspecific chemical groups known in the art and when administered into anindividual these groups undergo biotransformation to give the parentcompound. Pro-drugs can thus be viewed as compounds of the inventioncontaining one or more specialized non-toxic protective groups used in atransient manner to alter or to eliminate a property of the compound. Inone general aspect, the “pro-drug” approach is utilized to facilitateoral absorption. A thorough discussion is provided in T. Higuchi and V.Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A.C.S.Symposium Series; and in Bioreversible Carriers in Drug Design, ed.Edward B. Roche, American Pharmaceutical Association and Pergamon Press,1987, both of which are hereby incorporated by reference in theirentirety.

Some embodiments of the present invention include a method of producinga pharmaceutical composition for “combination-therapy” comprisingadmixing at least one compound according to any of the compoundembodiments disclosed herein, together with at least one knownpharmaceutical agent as described herein and a pharmaceuticallyacceptable carrier.

In some embodiments the pharmaceutical agents is selected from the groupconsisting of: sulfonylureas, meglitinides, biguanides, α-glucosidaseinhibitors, peroxisome proliferators-activated receptor-γ (i.e., PPAR-γ)agonists, insulin, insulin analogues, HMG-CoA reductase inhibitors,cholesterol-lowering drugs (for example, fibrates that include:fenofibrate, bezafibrate, gemfibrozil, clofibrate and the like; bileacid sequestrants which include: cholestyramine, colestipol and thelike; and niacin), antiplatelet agents (for example, aspirin andadenosine diphosphate receptor antagonists that include: clopidogrel,ticlopidine and the like), angiotensin-converting enzyme inhibitors,angiotensin II receptor antagonists and adiponectin.

It is noted that when the RUP3 receptor modulators are utilized asactive ingredients in a pharmaceutical composition, these are notintended for use only in humans, but in other non-human mammals as well.Indeed, recent advances in the area of animal health-care mandate thatconsideration be given for the use of active agents, such as RUP3receptor modulators, for the treatment of obesity in domestic animals(e.g., cats and dogs), and RUP3 receptor modulators in other domesticanimals where no disease or disorder is evident (e.g., food-orientedanimals such as cows, chickens, fish, etc.). Those of ordinary skill inthe art are readily credited with understanding the utility of suchcompounds in such settings.

Combination Therapy

In the context of the present invention, a compound as described hereinor pharmaceutical composition thereof can be utilized for modulating theactivity of RUP3 receptor mediated diseases, conditions and/or disordersas described herein. Examples of modulating the activity of RUP3receptor mediated diseases include the treatment of metabolic relateddisorders. Metabolic related disorders includes, but not limited to,hyperlipidemia, type 1 diabetes, type 2 diabetes mellitus, andconditions associated therewith, such as, but not limited to coronaryheart disease, ischemic stroke, restenosis after angioplasty, peripheralvascular disease, intermittent claudication, myocardial infarction (e.g.necrosis and apoptosis), dyslipidemia, post-prandial lipemia, conditionsof impaired glucose tolerance (IGT), conditions of impaired fastingplasma glucose, metabolic acidosis, ketosis, arthritis, obesity,osteoporosis, hypertension, congestive heart failure, left ventricularhypertrophy, peripheral arterial disease, diabetic retinopathy, maculardegeneration, cataract, diabetic nephropathy, glomerulosclerosis,chronic renal failure, diabetic neuropathy, metabolic syndrome, syndromeX, premenstrual syndrome, coronary heart disease, angina pectoris,thrombosis, atherosclerosis, myocardial infarction, transient ischemicattacks, stroke, vascular restenosis, hyperglycemia, hyperinsulinemia,hyperlipidemia, hypertrygliceridemia, insulin resistance, impairedglucose metabolism, conditions of impaired glucose tolerance, conditionsof impaired fasting plasma glucose, obesity, erectile dysfunction, skinand connective tissue disorders, foot ulcerations and ulcerativecolitis, endothelial dysfunction and impaired vascular compliance. Insome embodiments, metabolic related disorders include type I diabetes,type II diabetes, inadequate glucose tolerance, insulin resistance,hyperglycemia, hyperlipidemia, hypertriglyceridemia,hypercholesterolemia, dyslipidemia and syndrome X. Other examples ofmodulating the activity of RUP3 receptor mediated diseases include thetreatment of obesity and/or overweight by decreasing food intake,inducing satiation (i.e., the feeling of fullness), controlling weightgain, decreasing body weight and/or affecting metabolism such that therecipient loses weight and/or maintains weight.

While the compounds of the invention can be administered as the soleactive pharmaceutical agent (i.e., mono-therapy), they can also be usedin combination with other pharmaceutical agents (i.e.,combination-therapy) for the treatment of thediseases/conditions/disorders described herein. Therefore, anotheraspect of the present invention includes methods of prophylaxis and/ortreatment of a metabolic related disorder or a weight related disorder,such as obesity, comprising administering to an individual in need ofprophylaxis and/or treatment a therapeutically effective amount of acompound of the present invention in combination with one or moreadditional pharmaceutical agent as described herein.

Suitable pharmaceutical agents that can be used in combination with thecompounds of the present invention include anti-obesity agents such asapolipoprotein-B secretion/microsomal triglyceride transfer protein(apo-B/MTP) inhibitors, MCR-4 agonists, cholescystokinin-A (CCK-A)agonists, serotonin and norepinephrine reuptake inhibitors (for example,sibutramine), sympathomimetic agents, β3 adrenergic receptor agonists,dopamine agonists (for example, bromocriptine), melanocyte-stimulatinghormone receptor analogs, cannabinoid 1 receptor antagonists [forexample, SR141716:N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide],melanin concentrating hormone antagonists, leptons (the OB protein),leptin analogues, leptin receptor agonists, galanin antagonists, lipaseinhibitors (such as tetrahydrolipstatin, i.e., Orlistat), anorecticagents (such as a bombesin agonist), Neuropeptide-Y antagonists,thyromimetic agents, dehydroepiandrosterone or an analogue thereof,glucocorticoid receptor agonists or antagonists, orexin receptorantagonists, urocortin binding protein antagonists, glucagon-likepeptide-1 receptor agonists, ciliary neutrotrophic factors (such asAxokine™ available from Regeneron Pharmaceuticals, Inc., Tarrytown, N.Y.and Procter & Gamble Company, Cincinnati, Ohio), human agouti-relatedproteins (AGRP), ghrelin receptor antagonists, histamine 3 receptorantagonists or reverse agonists, neuromedin U receptor agonists,noradrenergic anorectic agents (for example, phentermine, mazindol andthe like) and appetite suppressants (for example, bupropion).

Other anti-obesity agents, including the agents set forth infra, arewell known, or will be readily apparent in light of the instantdisclosure, to one of ordinary skill in the art.

In some embodiments, the anti-obesity agents are selected from the groupconsisting of orlistat, sibutramine, bromocriptine, ephedrine, leptin,and pseudoephedrine. In a further embodiment, compounds of the presentinvention and combination therapies are administered in conjunction withexercise and/or a sensible diet.

It will be understood that the scope of combination-therapy of thecompounds of the present invention with other anti-obesity agents,anorectic agents, appetite suppressant and related agents is not limitedto those listed above, but includes in principle any combination withany pharmaceutical agent or pharmaceutical composition useful for thetreatment of overweight and obese individuals.

Other suitable pharmaceutical agents, in addition to anti-obesityagents, that can be used in combination with the compounds of thepresent invention include agents useful in the treatment of metabolicrelated disorders and/or concomitant diseases thereof. For example, butnot limited to, congestive heart failure, type I diabetes, type IIdiabetes, inadequate glucose tolerance, insulin resistance,hyperglycemia, hyperlipidemia, hypertriglyceridemia,hypercholesterolemia, dyslipidemia, syndrome X, retinopathy, nephropathyand neuropathy. Treatment of one or more of the diseases cited hereininclude the use of one or more pharmaceutical agents known in the artbelonging to the classes of drugs referred to, but not limited to, thefollowing: sulfonylureas, meglitinides, biguanides, α-glucosidaseinhibitors, peroxisome proliferators-activated receptor-γ (i.e., PPAR-γ)agonists, insulin, insulin analogues, HMG-CoA reductase inhibitors,cholesterol-lowering drugs (for example, fibrates that include:fenofibrate, bezafibrate, gemfibrozil, clofibrate and the like; bileacid sequestrants which include: cholestyramine, colestipol and thelike; and niacin), antiplatelet agents (for example, aspirin andadenosine diphosphate receptor antagonists that include: clopidogrel,ticlopidine and the like), angiotensin-converting enzyme inhibitors,angiotensin II receptor antagonists, adiponectin and the like. Inaccordance to one aspect of the present invention, a compound of thepresent can be used in combination with a pharmaceutical agent or agentsbelonging to one or more of the classes of drugs cited herein.

It will be understood that the scope of combination-therapy of thecompounds of the present invention with other pharmaceutical agents isnot limited to those listed herein, supra or infra, but includes inprinciple any combination with any pharmaceutical agent orpharmaceutical composition useful for the treatment of diseases,conditions or disorders that are linked to metabolic related disorders.

Some embodiments of the present invention include methods of treatmentof a disease, disorder, condition or complication thereof as describedherein, comprising administering to an individual in need of suchtreatment a therapeutically effective amount or dose of a compound ofthe present invention in combination with at least one pharmaceuticalagent selected from the group consisting of: sulfonylureas,meglitinides, biguanides, α-glucosidase inhibitors, peroxisomeproliferators-activated receptor-γ (i.e., PPAR-γ) agonists, insulin,insulin analogues, HMG-CoA reductase inhibitors, cholesterol-loweringdrugs (for example, fibrates that include: fenofibrate, bezafibrate,gemfibrozil, clofibrate and the like; bile acid sequestrants whichinclude: cholestyramine, colestipol and the like; and niacin),antiplatelet agents (for example, aspirin and adenosine diphosphatereceptor antagonists that include: clopidogrel, ticlopidine and thelike), angiotensin-converting enzyme inhibitors, angiotensin II receptorantagonists and adiponectin. In some embodiments, methods of the presentinvention include compounds of the present invention and thepharmaceutical agents are administered separately. In furtherembodiments, compounds of the present invention and the pharmaceuticalagents are administered together.

Suitable pharmaceutical agents that can be used in conjunction withcompounds of the present invention include sulfonylureas. Thesulfonylureas (SU) are drugs which promote secretion of insulin frompancreatic β cells by transmitting signals of insulin secretion via SUreceptors in the cell membranes. Examples of the sulfonylureas includeglyburide, glipizide, glimepiride and other sulfonylureas known in theart.

Suitable pharmaceutical agents that can be used in conjunction withcompounds of the present invention include the meglitinides. Themeglitinides are benzoic acid derivatives represent a novel class ofinsulin secretagogues. These agents target postprandial hyperglycemiaand show comparable efficacy to sulfonylureas in reducing HbA1c.Examples of meglitinides include repaglinide, nateglinide and othermeglitinides known in the art.

Suitable pharmaceutical agents that can be used in conjunction withcompounds of the present invention include the biguanides. Thebiguanides represent a class of drugs that stimulate anaerobicglycolysis, increase the sensitivity to insulin in the peripheraltissues, inhibit glucose absorption from the intestine, suppress ofhepatic gluconeogenesis, and inhibit fatty acid oxidation. Examples ofbiguanides include phenformin, metformin, buformin, and biguanides knownin the art.

Suitable pharmaceutical agents that can be used in conjunction withcompounds of the present invention include the α-glucosidase inhibitors.The α-glucosidase inhibitors competitively inhibit digestive enzymessuch as α-amylase, maltase, α-dextrinase, sucrase, etc. in the pancreasand or small intestine. The reversible inhibition by α-glucosidaseinhibitors retard, diminish or otherwise reduce blood glucose levels bydelaying the digestion of starch and sugars. Examples of α-glucosidaseinhibitors include acarbose, N-(1,3-dihydroxy-2-propyl)valiolamine(generic name; voglibose), miglitol, and α-glucosidase inhibitors knownin the art.

Suitable pharmaceutical agents that can be used in conjunction withcompounds of the present invention include the peroxisomeproliferators-activated receptor-γ (i.e., PPAR-γ) agonists. Theperoxisome proliferators-activated receptor-γ agonists represent a classof compounds that activates the nuclear receptor PPAR-γ and thereforeregulate the transcription of insulin-responsive genes involved in thecontrol of glucose production, transport and utilization. Agents in theclass also facilitate the regulation of fatty acid metabolism. Examplesof PPAR-γ agonists include rosiglitazone, pioglitazone, tesaglitazar,netoglitazone, GW-409544, GW-501516 and PPAR-γ agonists known in theart.

Suitable pharmaceutical agents that can be used in conjunction withcompounds of the present invention include the HMG-CoA reductaseinhibitors. The HMG-CoA reductase inhibitors are agents also referred toas Statin compounds that belong to a class of drugs that lower bloodcholesterol levels by inhibiting hydroxymethylglutalyl CoA (HMG-CoA)reductase. HMG-CoA reductase is the rate-limiting enzyme in cholesterolbiosynthesis. The statins lower serum LDL concentrations by upregulatingthe activity of LDL receptors and are responsible for clearing LDL fromthe blood. Some representative examples the statin compounds includerosuvastatin, pravastatin and its sodium salt, simvastatin, lovastatin,atorvastatin, fluvastatin, cerivastatin, rosuvastatin, pitavastatin,BMS's “superstatin”, and HMG-CoA reductase inhibitors known in the art.

Suitable pharmaceutical agents that can be used in conjunction withcompounds of the present invention include the Fibrates. Fibratecompounds belong to a class of drugs that lower blood cholesterol levelsby inhibiting synthesis and secretion of triglycerides in the liver andactivating a lipoprotein lipase. Fibrates have been known to activateperoxisome proliferators-activated receptors and induce lipoproteinlipase expression. Examples of fibrate compounds include bezafibrate,beclobrate, binifibrate, ciplofibrate, clinofibrate, clofibrate,clofibric acid, etofibrate, fenofibrate, gemfibrozil, nicofibrate,pirifibrate, ronifibrate, simfibrate, theofibrate, and fibrates known inthe art.

Suitable pharmaceutical agents that can be used in conjunction withcompounds of the present invention include the angiotensin convertingenzyme (ACE) inhibitors. The angiotensin converting enzyme inhibitorsbelong to the class of drugs that partially lower blood glucose levelsas well as lowering blood pressure by inhibiting angiotensin convertingenzymes. Examples of the angiotensin converting enzyme inhibitorsinclude captopril, enalapril, alacepril, delapril; ramipril, lisinopril,imidapril, benazepril, ceronapril, cilazapril, enalaprilat, fosinopril,moveltopril, perindopril, quinapril, spirapril, temocapril,trandolapril, and angiotensin converting enzyme inhibitors known in theart.

Suitable pharmaceutical agents that can be used in conjunction withcompounds of the present invention include the angiotensin II receptorantagonists. Angiotensin II receptor antagonists target the angiotensinII receptor subtype 1 (i.e., AT1) and demonstrate a beneficial effect onhypertension. Examples of angiotensin II receptor antagonists includelosartan (and the potassium salt form), and angiotensin II receptorantagonists known in the art.

Suitable pharmaceutical agents that can be used in conjunction withcompounds of the present invention include the squalene synthesisinhibitors. Squalene synthesis inhibitors belong to a class of drugsthat lower blood cholesterol levels by inhibiting synthesis of squalene.Examples of the squalene synthesis inhibitors include(S)-α-[Bis[2,2-dimethyl-1-oxopropoxy)methoxy]phosphinyl]-3-phenoxybenzenebutanesulfonicacid, mono potassium salt (BMS-188494) and squalene synthesis inhibitorsknown in the art.

Suitable pharmaceutical agents that can be used in conjunction withcompounds of the present invention include, but not limited to, amylinagonists (for example, pramlintide), insulin secretagogues (for example,GLP-1 agonists; exendin-4; insulinotropin (NN2211); dipeptyl peptidaseinhibitors (for example, NVP-DPP-728), acyl CoA cholesterolacetyltransferase inhibitors (for example, Ezetimibe, eflucimibe, andlike compounds), cholesterol absorption inhibitors (for example,ezetimibe, pamaqueside and like compounds), cholesterol ester transferprotein inhibitors (for example, CP-529414, JTT-705, CETi-1, and likecompounds), microsomal triglyceride transfer protein inhibitors (forexample, implitapide, and like compounds), cholesterol modulators (forexample, NO-1886, and like compounds), bile acid modulators (forexample, GT103-279 and like compounds), insulin signalling pathwaymodulators, like inhibitors of protein tyrosine phosphatases (PTPases),non-small mol. mimetic compds. and inhibitors ofglutamine-fructose-6-phosphate amidotransferase (GFAT), compds.influencing a dysregulated hepatic glucose prodn., like inhibitors ofglucose-6-phosphatase (G6 Pase), inhibitors offructose-1,6-bisphosphatase (F-1,6-BPase), inhibitors of glycogenphosphorylase (GP), glucagon receptor antagonists and inhibitors ofphosphoenolpyruvate carboxykinase (PEPCK), pyruvate dehydrogenase kinase(PDHK) inhibitors, insulin sensitivity enhancers, insulin secretionenhancers, inhibitors of gastric emptying, (α₂-adrenergic antagonistsand retinoid X receptor (RXR) agonists.

Suitable pharmaceutical agents that can be used in conjunction withcompounds of the present invention include inhibitors of dipeptidylpeptidase IV (DPP-IV). Examples of DPP-IV inhibitors includevaline-pyrrolidide, 3-(L-Isoleucyl)thiazolidine,1-[2-[5-cyanopyridin-2-yl)amino]ethylamino]acetyl-2-cyano-(S)-pyrrolidine(NVP-DPP728),3(R)-Amino-1-[3-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one(MK-0431),(1-[[3-hydroxy-1-adamantyl)amino]acetyl]-2-cyano-(S)-pyrrolidine(LAF237),(1S,3S,5S)-2-[2(S)-Amino-2-(3-hydroxyadamantan-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile(BMS477118), [1-[2(S)-Amino-3-methylbutyryl]pyrrolidin-2(R)-yl]boronicacid (PT-100), GSK-823093, PSN-9301, T-6666, SYR-322, SYR-619 and DPP-IVinhibitors known in the art. Exemplary DPP-IV inhibitors known in theart include but are not limited to those disclosed in the followingInternational Applications: WO 2005/075426, WO 2005/072530, WO2005/063750, WO 2005/058849, WO 2005/047297, WO 2005/042488, WO2005/040095, WO 2005/033099, WO 2005/030751, WO 2005/030127, WO2005/026148, WO 2005/025554, WO 2005/023762, WO 2005/020920, WO03/04498, WO 00/34241, WO 98/19998 and WO 97/40832. In some embodiments,the DPP-IV inhibitor is a selective DPP-IV inhibitor, having selectivityfor DPP-IV over closely related peptidases, such as one or more ofpost-proline-cleaving enzyme (PPCE), dipeptidyl peptidase II (DPP-II),dipeptidyl peptidase 8 (DPP-8) and dipeptidyl peptidase 9 (DPP-9).

In accordance with the present invention, the combination can be used bymixing the respective active components either all together orindependently with a physiologically acceptable carrier, excipient,binder, diluent, etc., as described herein above, and administering themixture or mixtures either orally or non-orally as a pharmaceuticalcomposition. When a compound or a mixture of compounds of the presentinvention are administered as a combination therapy with another activecompound the therapeutic agents can be formulated as a separatepharmaceutical compositions given at the same time or at differenttimes, or the therapeutic agents can be given as a single composition.

Other Utilities

Another object of the present invention relates to radio-labeledcompounds as described herein that would be useful not only inradio-imaging but also in assays, both in vitro and in vivo, forlocalizing and quantitating the RUP3 receptor in tissue samples,including human, and for identifying RUP3 receptor ligands by inhibitionbinding of a radio-labeled compound. It is a further object of thisinvention to develop novel RUP3 receptor assays of which comprise suchradio-labeled compounds.

The present invention embraces isotopically-labeled compounds of Formula(Ia) and any subgenera herein, such as but not limited to, Formula (Ia)through Formula (IIi). An “isotopically” or “radio-labeled” compoundsare those which are identical to compounds disclosed herein, but for thefact that one or more atoms are replaced or substituted by an atomhaving an atomic mass or mass number different from the atomic mass ormass number typically found in nature (i.e., naturally occurring).Suitable radionuclides that may be incorporated in compounds of thepresent invention include but are not limited to ²H (also written as Dfor deuterium), ³H (also written as T for tritium), ¹¹C, ¹³C, ¹⁴C, ¹³N,¹⁵N, ¹⁵O, ¹⁷O, ¹⁸F, 35S, ³⁶Cl, ⁸²Br, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br, ¹²³I, ¹²⁴I, ¹²⁵Iand ¹³¹I. The radionuclide that is incorporated in the instantradio-labeled compounds will depend on the specific application of thatradio-labeled compound. For example, for in vitro RUP3 receptor labelingand competition assays, compounds that incorporate ³H, ¹⁴C, ⁸²Br, ¹²⁵I,¹³¹I, ³⁵S or will generally be most useful. For radio-imagingapplications ¹¹C, ¹⁸F, ¹²⁵I, ¹²³I, ¹²⁴I, ¹³¹I, ⁷⁵Br, ⁷⁶Br or ⁷⁷Br willgenerally be most useful.

It is understood that a “radio-labeled” or “labeled compound” is acompound of present invention that has incorporated at least oneradionuclide; in some embodiments the radionuclide is selected from thegroup consisting of ³H, ¹⁴C, ¹²⁵I, ³⁵S and ⁸²Br.

Certain isotopically-labeled compounds of the present invention areuseful in compound and/or substrate tissue distribution assays. In someembodiments the radionuclide ³H and/or ¹⁴C isotopes are useful in thesestudies. Further, substitution with heavier isotopes such as deuterium(i.e., ²H) may afford certain therapeutic advantages resulting fromgreater metabolic stability (e.g., increased in vivo half-life orreduced dosage requirements) and hence may be preferred in somecircumstances. Isotopically labeled compounds of the present inventioncan generally be prepared by following procedures analogous to thosedisclosed in the Schemes supra and Examples infra, by substituting anisotopically labeled reagent for a non-isotopically labeled reagent.Other synthetic methods that are useful are discussed infra. Moreover,it should be understood that all of the atoms represented in thecompounds of the invention can be either the most commonly occurringisotope of such atoms or the more scarce radio-isotope ornonradio-active isotope.

Synthetic methods for incorporating radio-isotopes into organiccompounds are applicable to compounds of the invention and are wellknown in the art. These synthetic methods, for example, incorporatingactivity levels of tritium into target molecules, are as follows:

A. Catalytic Reduction with Tritium Gas—This procedure normally yieldshigh specific activity products and requires halogenated or unsaturatedprecursors.

B. Reduction with Sodium Borohydride [³H]—This procedure is ratherinexpensive and requires precursors containing reducible functionalgroups such as aldehydes, ketones, lactones, esters, and the like.

C. Reduction with Lithium Aluminum Hydride [³H]—This procedure offersproducts at almost theoretical specific activities. It also requiresprecursors containing reducible functional groups such as aldehydes,ketones, lactones, esters, and the like.

D. Tritium Gas Exposure Labeling—This procedure involves exposingprecursors containing exchangeable protons to tritium gas in thepresence of a suitable catalyst.

E. N-Methylation using Methyl Iodide [³H]—This procedure is usuallyemployed to prepare O-methyl or N-methyl (3H) products by treatingappropriate precursors with high specific activity methyl iodide (3H).This method in general allows for higher specific activity, such as forexample, about 70-90 Ci/mmol.

Synthetic methods for incorporating activity levels of ¹²⁵I into targetmolecules include:

A. Sandmeyer and like reactions—This procedure transforms an aryl orheteroaryl amine into a diazonium salt, such as a tetrafluoroboratesalt, and subsequently to ¹²⁵I labeled compound using Na ¹²⁵I. Arepresented procedure was reported by Zhu, D.-G. and co-workers in J.Org. Chem. 2002, 67, 943-948.

B. Ortho ¹²⁵Iodination of phenols—This procedure allows for theincorporation of ¹²⁵I at the ortho position of a phenol as reported byCollier, T. L. and co-workers in J. Labeled Compd Radiopharm. 1999, 42,S264-S266.

C. Aryl and heteroaryl bromide exchange with ¹²⁵I—This method isgenerally a two step process. The first step is the conversion of thearyl or heteroaryl bromide to the corresponding tri-alkyltinintermediate using for example, a Pd catalyzed reaction [i.e. Pd(Ph₃P)4]or through an aryl or heteroaryl lithium, in the presence of atri-alkyltinhalide or hexaalkylditin [e.g., (CH₃)₃SnSn(CH₃)₃]. Arepresented procedure was reported by Bas, M.-D. and co-workers in J.Labeled Compd Radiopharin. 2001, 44, S280-S282.

A radio-labeled RUP3 receptor compound of present invention can be usedin a screening assay to identify/evaluate compounds. In general terms, anewly synthesized or identified compound (i.e., test compound) can beevaluated for its ability to reduce binding of the “radio-labeledcompound” of the present invention to the RUP3 receptor. Accordingly,the ability of a test compound to compete with the “radio-labeledcompound” of the present invention for the binding to the RUP3 receptordirectly correlates to its binding affinity.

The labeled compounds of the present invention bind to the RUP3receptor. In one embodiment the labeled compound has an IC₅₀ less thanabout 500 μM, in another embodiment the labeled compound has an IC₅₀less than about 100 μM, in yet another embodiment the labeled compoundhas an IC₅₀ less than about 10 μM, in yet another embodiment the labeledcompound has an IC₅₀ less than about 1 μM, and in still yet anotherembodiment the labeled inhibitor has an IC₅₀ less than about 0.1 μM.

Other uses of the disclosed receptors and methods will become apparentto those in the art based upon, inter alia, a review of this disclosure.

As will be recognized, the steps of the methods of the present inventionneed not be performed any particular number of times or in anyparticular sequence. Additional objects, advantages, and novel featuresof this invention will become apparent to those skilled in the art uponexamination of the following examples thereof, which are intended to beillustrative and not intended to be limiting.

EXAMPLES

The examples are provided to further define the invention without,however, limiting the invention to the specifics of these examples.

Example 1

96-well Cyclic AMP Membrane Assay for RUP3

Materials:

-   1) Adenlyl cyclase Activation Flashplate Assay kit from Perkin    Elmer—96 wells (SMP004B) and ¹²⁵I tracer (NEX130) which comes with    the kit. Keep in refrigerator, in a box, and do not expose the    Flashplates to light.-   2) Phosphocreatine—Sigma P-7936-   3) Creatine Phosphokinase—Sigma C-3755-   4) GTP—Sigma G-8877-   5) ATP—Sigma A-2383-   6) IBMX—Sigma 1-7018-   7) Hepes—1M solution in distilled water—Gibco #15630080-   8) MgCl₂—Sigma M-1028—1M Solution-   9) NaCl—Sigma —S6546—5M Solution-   10) Bradford Protein Assay Kit—Biorad # 5000001-   11) Proclin 300—Sigma #4-8126    Binding Buffer—filter through 45-micron Nalgene filter and keep in    refrigerator. All buffers and membranes should be kept cold (in ice    bucket) while performing assay.    20 mM Hepes, pH 7.4    1 mM MgCl₂    100 mM NaCl    2× Regeneration Buffer (make in binding buffer):    20 mM Phosphocreatine (1.02 gm/200 ml binding buffer)    20 units Creatine phosphokinase (4 mg/200 ml)    20 uM GTP (make up 10.46 mg/ml in binding buffer and add 200 ul/200    ml)    0.2 mM ATP (22.04 mg/200 ml)    100 mM IBMX (44.4 mg IBMX dissolved in 1 ml 100% DMSO first and then    add the entire amount to 200 ml of buffer).    Regeneration buffer can be aliquotted into 40-45 ml portions (in 50    ml sterile tubes) and kept frozen for up to 2 months. Simply put the    tube in a beaker with room temperature water to thaw out the    regeneration buffer on the day of the assay.    A. Assay procedure    -   1) Pipet 50 ul regeneration buffer in all 96 wells using Matrix        1250 8-channel pipettor.    -   2) Pipet 5 ul DMSO in columns 1 and columns 11 and 12.    -   3) Pipet 50 ul cAMP standards in columns 11 and 12 in this        format: 50 pmole/well for row A, 25 pmole/well for row B, 12.5        pmol/well for row C, 5 picomol/well for row D, 2.5 pmole/well        for row E, 1.25 pmole/well for row F, 0.5 pmole/well for row G,        and 0 pmole/well (buffer only) for row H.    -   4) Pipet 5 ul compounds from each well of a compound dilution        plate, for IC50s, using the following dilution scheme:        -   Well H: 400 uM compound (final concentration of compound in            reaction mix=5/100×400 uM=20 uM        -   Well G: 1:10 dilution of Well H (i.e. 5 ul compound from            well H+45 ul 100% DMSO) (final concentration=2 uM)        -   Well F: 1:10 dilution of well G (final concentration=0.2 uM)        -   Well E: 1:10 dilution of well F (final concentration=0.02            uM)        -   Well D: 1:10 dilution of well E (final concentration=0.002            uM)        -   Well C: 1:10 dilution of well D (final concentration=0.0002            uM        -   Well B: 1:10 dilution of well C (final concentration=0.00002            uM)        -   Well A: 1:10 dilution of well B (final            concentration=0.000002 uM)    -   IC₅₀s or EC₅₀s are done in triplicate. One Flashplate can        therefore be set up to handle 3 compounds. (i.e., columns 2, 3,        and 4 are for compound #1, columns 5, 6, and 7 are for compound        #2, and columns 8, 9, and 10 are for compound #3.)    -   5) Add 50 ul of RUP3 membranes to all wells in Columns 2 to 10.        (Prior to the start of the assay, the frozen membrane pellets        for both RUP3 and CMV (cells transfected with an expression        plasmid containing no RUP3 sequences), are suspended in binding        buffer, usually 1 ml binding buffer for 1 plate of membranes.        The membranes are kept in ice all the time, and a polytron        (Brinkmann polytron, model # PT-3100) is used (setting 6-7, for        15-20 seconds) to obtain a homogeneous membrane suspension.)        Protein concentration is determined by Bradford protein assay        kit using instructions given in the kit, using the standard        supplied with the kit as a reference. The protein concentration        of the membranes is adjusted with binding buffer, so that 50 ul        membranes=15 ug protein (i.e. 0.3 mg/ml protein).    -   6) In column 1, Wells A, B, C, and D, add 50 ul RUP3 membranes.        To wells E, F, G, and H, add 50 ul CMV membranes, (CMV membranes        being of the same protein concentration as the RUP3 membranes).    -   7) Incubate 1 hour at room temperature with agitation on a        rotating platform shaker. Cover with foil while shaking.    -   8) After 1 hour, add (to all 96 wells), 100 ul of the ¹²⁵I        tracer in detection buffer supplied with the Flashplate kit plus        proclin, made up in the following manner:    -   Pipet per 10 ml per Flashplate: 100 ml of detection buffer+1 ml        ¹²⁵I+0.2 ml of Proclin (the proclin helps to stop the production        of cAMP). Make a smaller quantity of detection buffer mix if you        have fewer plates.    -   9) Shake the plates on a rotating platform shaker for 2 hours,        covering the plates with lead sheeting.    -   10) Seal the plates with the plastic film sealers provided with        the Flashplate kit.    -   11) Count the plates using a TRILUX 1450 Microbeta Counter. See        the door of the counter to determine which counting protocol to        use.    -   12) Data is analyzed on the Arena Database according to the RUP3        non-fusion, IC₅₀ EC₅₀ for 96-well cAMP membrane assay, and the        compound numbers and the concentrations of compounds must be        entered by the user.        B. Membrane Cyclase Criteria

1) Signal to Noise:

-   -   An acceptable signal-to-noise ratio for RUP3 can vary from 4        to 6. The raw cpms are approximately 1800 to 2500 for RUP3 and        3500-4500 for CMV. The cpm (or ultimately pmoles of cAMP/well)        cannot be outside the standard curve, and should not approach        well A of the standard curve (50 pmole/well) and well H (no        cAMP). Generally, the pmoles of cAMP produced by RUP3 receptor        are around 11 to 13 pmole/well (for 15 ug/well protein), and for        CMV are between 2 to 3 pmole/well (for 15 ug protein/well).

2) Standard Curve:

-   -   The slope should be linear and the error bars for duplicates        should be very small. The receptor and CMV controls cannot be        off scale of the standard curve, as described above. If the        receptor controls are off the high end of the standard curve,        i.e. 50 pmole/well or higher, one must repeat the experiment        using less protein. However, such a case has not been observed        with transiently transfected RUP3 membranes (10 ug DNA/15 cm        plate, using 60 ul Lipofectamine, and preparing membranes after        24 hour of transfection.)    -   3) The IC₅₀ or EC₅₀ curve should be at 100% (+ or −20%) of        control RUP3 membranes at the top, and should go down to 0 (or        up to 20%) at the bottom. The standard error of the triplicate        determinations should be + or −10%.        C. Stimulation of cAMP in HIT-T15 Cells

HIT-T15 (ATCC CRL# 1777) is an immortalized hamster insulin-producingcell line. These cells express RUP3 and therefore can be used to assessthe ability of RUP3 ligands to stimulate or inhibit cAMP accumulationvia its endogenously expressed receptor. In this assay, cells are grownto 80% confluence and then distributed into a 96-well Flashplate (50,000cells/well) for detection of cAMP via a “cAMP Flashplate Assay” (NEN,Cat # SMP004). Briefly, cells are placed into anti-cAMP antibody-coatedwells that contain either vehicle, the test ligand(s) at a concentrationof interest, or 1 uM forskolin. The latter is a direct activator ofadenylyl cyclase and serves as a positive control for stimulation ofcAMP in HIT-T15 cells. All conditions are tested in triplicate. After a1 hour incubation to allow for stimulation of cAMP, a Detection Mixcontaining ¹²⁵I-cAMP is added to each well and the plate is allowed toincubate for another 1 hour. The wells are then aspirated to removeunbound ¹²⁵I-cAMP. Bound ¹²⁵I-cAMP is detected using a Wallac MicrobetaCounter. The amount of cAMP in each sample is determined by comparisonto a standard curve, obtained by placing known concentrations of cAMP insome wells on the plate.

D. Stimulation of Insulin Secretion in MIT-T15 Cells

It is known that stimulation of cAMP in HIT-T15 cells causes an increasein insulin secretion when the glucose concentration in the culture mediais changed from 3 mM to 15 mM. Thus, RUP3 ligands can also be tested fortheir ability to stimulate glucose-dependent insulin secretion (GSIS) inHIT-T15 cells. In this assay, 30,000 cells/well in a 12-well plate areincubated in culture media containing 3 mM glucose and no serum for 2hours. The media is then changed; wells receive media containing either3 mM or 15 mM glucose, and in both cases the media contains eithervehicle (DMSO) or RUP3 ligand at a concentration of interest. Some wellsreceive media containing 1 uM forskolin as a positive control. Allconditions are tested in triplicate. Cells are incubated for 30 minutes,and the amount of insulin secreted into the media is determined byELISA, using a kit from either Peninsula Laboratories (Cat # ELIS-7536)or Crystal Chem Inc. (Cat # 90060).

E. Stimulation of Insulin Secretion in Isolated Rat Islets

As with HIT-T15 cells, it is known that stimulation of cAMP in isolatedrat islets causes an increase in insulin secretion when the glucoseconcentration in the culture media is changed from 60 mg/dl to 300mg/dl. RUP3 is an endogenously expressed GPCR in the insulin-producingcells of rat islets. Thus, RUP3 ligands can also be tested for theirability to stimulate GSIS in rat islet cultures. This assay is performedas follows:

-   -   A. Select 75-150 islet equivalents (EQ) for each assay condition        using a dissecting microscope. Incubate overnight in low-glucose        culture medium. (Optional.)    -   B. Divide the islets evenly into triplicate samples of 2540        islet equivalents per sample.

Transfer to 40 μm mesh sterile cell strainers in wells of a 6-well platewith 5 ml of low (60 mg/dl) glucose Krebs-Ringers Buffer (KRB) assaymedium.

-   -   C. Incubate 30 minutes (1 hour if overnight step skipped) at        37° C. and 5% CO₂. Save the supernatants if a positive control        for the RIA is desired.    -   D. Move strainers with islets to new wells with 5 ml/well low        glucose KRB. This is the second pre-incubation and serves to        remove residual or carryover insulin from the culture medium.        Incubate 30 minutes.    -   E. Move strainers to next wells (Low 1) with 4 or 5 ml low        glucose KRB. Incubate 37° C. for 30 minutes. Collect        supernatants into low-binding polypropylene tubes pre-labelled        for identification and keep cold.    -   F. Move strainers to high glucose wells (300 mg/dl, which is        equivalent to 16.7 mM). Incubate and collect supernatants as        before. Rinse islets in their strainers in low-glucose to remove        residual insulin. If the rinse if to be collected for analysis,        use one rinse well for each condition (i.e. set of triplicates.)    -   G. Move strainers to final wells with low-glucose assay medium        (Low 2). Incubate and collect supernatants as before.    -   H. Keeping cold, centrifuge supernatants at 1800 rpm for 5        minutes@ 4-8° C. to remove small islets/islet pieces that escape        the 40 mm mesh. Remove all but lower 0.5-1 ml and distribute in        duplicate to pre-labelled low-binding tubes. Freeze and store at        <−20° C. until insulin concentrations can be determined.    -   I. Insulin determinations are done as above, or by Linco Labs as        a custom service, using their rat insulin RIA (Cat. # RI-13K).

Example 2

A. RT-PCR Analysis of RUP3 Expression in Human Tissues (FIG. 1A).

RT-PCR was applied to determine the tissue distribution of RUP3.Oligonucleotides used for PCR had the following sequences: ZC47: (SEQ IDNO:3) 5′-CATTGCCGGGCTGTGGTTAGTGTC-3′ (forward primer),; ZC48: (SEQ IDNO:4) 5′-GGCATAGATGAGTGGGTTGAGCAG-3′ (reverse primer),;

and the human multiple tissue cDNA panels (MTC, Clontech) were used astemplates (1 ng cDNA per PCR amplification). Twenty-two (22) humantissues were analyzed. PCR was performed using Platinum PCR SuperMix(Life Technologies, Inc.; manufacture instructions were followed) in a50 μl reaction by the following sequences: step 1, 95° C. for 4 min;step 2, 95° C. for 1 min; step 3, 60° C. for 30 sec; step 4, 72° C. for1 min; and step 5, 72° C. for 7 min. Steps 2 through 4 were repeated 35times.

The resulting PCR reactions (15 □l) were loaded on a 1.5% agarose gel toanalyze the RT-PCR products, and a specific 466 base-pair DNA fragmentrepresenting RUP3 was specifically amplified from cDNA of pancreasorigin. Low expression was also evident in subregions of brain.

B. cDNA Dot-Blot Analysis of RUP3 Expression in Human Tissues (FIG. 1B).

Results from RT-PCR analysis were further confirmed in cDNA dot-blotanalysis. In this assay, a dot-blot membrane containing cDNA from 50human tissues (Clontech) was hybridized with a ³²P-radiolabelled DNAprobe having sequences derived from human RUP3. Hybridyzation signalswere seen in pancreas and fetal liver, suggesting these tissues expressRUP3. No significant expression was detected in other tissues analyzed.

C. Analysis of RUP3 by RT-PCR with Isolated Human Pancreatic Islets ofLangerhans (FIG. 1C).

Further analysis of RUP3 by RT-PCR with isolated human pancreatic isletsof Langerhans showed robust expression of RUP3 in islet cells but not incontrol samples.

D. Analysis of RUP3 Expression with cDNAs of Rat Origin by RT-PCR (FIG.1D).

RUP3 expression was further analyzed with cDNAs of rat origin by RT-PCRtechnique. Tissue cDNAs used for this assay were obtained from Clontechexcept those for hypothalamus and islets, which were prepared in house.Concentrations of each cDNA sample were normalized via a control RT-PCRanalysis of the house-keeping gene GAPDH before assaying for RUP3expression. Oligonucleotides used for PCR had the following sequences:

rat RUP3 (“rRUP3”) forward: 5′-CATGGGCCCTGCACCTTCTTTG-3′ (SEQ ID NO:5);

rRUP3 reverse: 5′-GCTCCGGATGGCTGATGATAGTGA-3′ (SEQ ID NO:6). PCR wasperformed using Platinum PCR SuperMix (Life Technologies, Inc.;manufacture instructions were followed) in a 50 μl reaction by thefollowing sequences: step 1, 95° C. for 4 min; step 2, 95° C. for 1 min;step 3, 60° C. for 30 sec; step 4, 72° C. for 1 min; and step 5, 72° C.for 7 min. Steps 2 through 4 were repeated 35 times.

The resulting PCR reactions (15 μl) were loaded on a 1.5% agarose gel toanalyze the RT-PCR products, and a specific 547 base-pair DNA fragmentrepresenting rat RUP3 was specifically amplified from cDNA of pancreasorigin, revealing a similar expression profile with human. Of particularnote, robust expression was seen in isolated islets and hypothalamus.

Example 3

RUP3 Protein Expression is Restricted to β Cell Lineage of PancreaticIslets (FIG. 2).

A. A Polyclonal Anti-RUP3 Antibody was Prepared in Rabbits (FIG. 2A).

Rabbits were immunized with an antigenic peptide with sequence derivedfrom rat RUP3 (“rRUP3”). The peptide sequence wasRGPERTRESAYHIVTISHPELDG (SEQ ID NO: 7) and shared 100% identity withmouse RUP3 in the corresponding region. A cysteine residue wasincorporated at the N-terminal end of this antigenic peptide tofacilitate KLH crosslinking before injecting into rabbits. The resultingantisera (“anti-rRUP3”) and the corresponding preimmune sera(“pre-rRUP3”) were tested for immune reactivity to mouse RUP3 inimmunobloting assays (lanes 1 though 4). In this assay, the GST-RUP3fusion protein was readily recognized by the anti-rRUP3 antisera (lane4), but not by the preimmune sera (lane 2). The immunoreactive signalcould be efficiently eliminated when the immunobloting assay wasperformed in the presence of excess antigenic peptide (lane 6).

B. RUP3 Expression in Insulin-Producing β Cells of Pancreatic Islets(FIG. 2B).

Rat pancreas was perfused with 4% paraformaldehyde (PFA) in PBS andembedded in OCT embedding medium. Ten micron sections were prepared,fixed on glass slides, and immunostained with either pre-rRUP3 (FIG. 2B,panel a) or with anti-rRUP3 antisera (FIG. 2B, panels c and e) followedby secondary staining with donkey anti-rabbit IgG conjugated to thefluorochrome Cy-3. Each section was also co-immunostained with amonoclonal anti-insulin antibody (Santa Cruz, FIG. 2B, panels b and d)in primary staining followed by a secondary staining with donkeyanti-mouse IgG conjugated with FITC, or with a goat anti-glucagonantibody (Santa Cruz, FIG. 2B, panel f) and donkey anti-goat IgG coupledto FITC. Immunofluorescent signals were examined under a fluorescentmicroscope. RUP3 was found expressed in insulin producing cells (panelsc and d), but not in glucagons producing cells (panels e and f). Thesedata demonstrated that RUP3 is expressed in β cells but not in β cellsof the rat pancreatic islets. Analogous results were obtained when mousepancreatic sections were investigated for RUP3 expression.

Example 4

Functional Activities of RUP3 In Vitro (FIG. 3).

It was established that RUP3 stimulates the production of cAMP bycotransfection of 293 cells with: (1) a CRE-Luciferase reporter, whereinthe ability to stimulate the production of firefly luciferase depends onincreased cAMP in cells, and (2) an expression plasmid encoding thehuman form of RUP3 (FIG. 3A). Note that cells co-transfected with anexpression plasmid containing no RUP3 sequences (“CMV” in FIG. 3A)produce very little luciferase activity, whereas cells transfected withan expression plasmid encoding RUP3 (“RUP3” in FIG. 3A) have at least a10-fold increase in luciferase activity. This indicates that RUP3stimulates the production of cAMP when introduced into 293 cells. Thisproperty of RUP3 is conserved across species, because hamster RUP3stimulates luciferase activity when introduced into 293 cells in amanner analogous to that described for human RUP3 (FIG. 3B).

It is established that, when cAMP is increased in insulin-producingcells of the pancreas, these cells exhibit an enhanced ability tosecrete insulin when glucose concentrations rise. To test whether RUP3might impart enhanced glucose-dependent insulin release, retroviruscontaining human RUP3 was used to generate Tu6 cells that express highlevels of RUP3. Tu6 cells produce insulin, but do not expressappreciable levels of RUP3 and do not normally exhibit an increase ininsulin release when increased glucose is present in the culture media.As shown in FIG. 3C, Tu6 cells transduced with a control virus thatcontains no receptor are still able to produce insulin, but do not showan increase in insulin secretion when the concentration of glucose inthe culture media is shifted from 1 mM to 16 mM. By contrast, Tu6 cellstransduced with RUP3-containing retrovirus display significantglucose-dependent insulin secretion (FIG. 3C).

Example 5

In Vivo Effects of RUP3 Agonists on Glucose Homeostasis in Mice.

A. Oral Glucose Tolerance Test (oGTT)

Male C57b1/6J mice at approximately 8 weeks of age were fasted for 18hours and randomly grouped (n=5) to receive a RUP3 agonist (eitherCompound B3 or B 124) at 1, 3 or 10 mg/Kg. Compounds were deliveredorally via a gavage needle (p.o., volume 10 mL/Kg). At time 0, levels ofblood glucose were assessed using a glucometer (Elite XL, Bayer), andmice were administered either vehicle (20%hydroxypropyl-beta-cyclodextrin) or test compound. Thirty minutes afteradministration of test compound, levels of blood glucose were againassessed, and mice were administered dextrose orally at a dose of 3g/Kg. Blood glucose measurements were then taken 20 min, 40 min, 60 minand 120 min after this time. Table 2 shows the mean percentageinhibition of glucose excursion for each dose of test compound, averagedacross the five animals in each treatment group. These resultsdemonstrated that the RUP3 agonists, including Compound 75, loweredblood glucose in a dose-dependent manner in mice after challenged withglucose. TABLE 2 Mean % Inhibition of Glucose Excursion Dose Compound 3mg/Kg 10 mg/Kg 75 22 34

Example 6

Generation of Tu6/RUP3 Stable Lines

To produce Tu6 cells that express RUP3 at high levels, a retrovirusbearing an expression cassette for RUP3 was generated. Briefly, RUP3coding sequence was cloned into the retroviral vector pLNCX2 (Clontech,Cat # 6102-1). The amphotropic packaging cell line PT-67 (Clontech,K1060-D) was then transfected with either the parental vector pLNCX2 orpLNCX2/RUP3 using Lipofectamine and stable lines were established usingguidelines provided by the PT-67 vendor. Retrovirus-containingsupernatant was obtained by collecting media from the resultant stablesaccording to the manufacturer's directions. Tu6 cells, in a 10 cm dish,were then infected with retrovirus by incubating in a solution of 1 mlviral supernatant/9 ml culture media containing 40 ug/ml polybrene for24 hours. The medium was then changed to culture media containing 300ug/ml G418. G418-resistant clones were ultimately created by virtue ofthe neomycin-resistance gene cassette present in the pLNCX2 vector, thusindicating the successful integration of retrovirus into the Tu6 genome.The expression of RUP3 in the Tu6/RUP3 G418-resistant colonies wasconfirmed by Northern blot.

Example 7

Insulin Secretion, Tu6 Stables

To measure insulin secretion from rodent insulin-producing cell lines,cells were first cultured overnight in serum-free, glucose-deficientmedia. The following morning, the cells were then placed in the samemedia supplemented with either 1 mM or 16 mM glucose. After anincubation of 4 hours, the media was collected and analyzed for insulincontent using a Rat Insulin Enzyme-Immunoassay (EIA) System (AmershamPharmacia Biotech, Cat. # RPN 2567). Typically, the assay was performedusing multiple dilutions of sample media in order to ensure that thesample measurements fell within the boundaries of the standard curve(generated using known amounts of insulin), as recommended by themanufacturer.

Example 8

Receptor Binding Assay

In addition to the methods described herein, another means forevaluating a test compound is by determining binding affinities to theRUP3 receptor. This type of assay generally requires a radiolabelledligand to the RUP3 receptor. Absent the use of known ligands for theRUP3 receptor and radiolabels thereof, compounds of Formula (Ia) can belabelled with a radioisotope and used in an assay for evaluating theaffinity of a test compound to the RUP3 receptor.

A radiolabelled RUP3 compound of Formula (Ia) can be used in a screeningassay to identify/evaluate compounds. In general terms, a newlysynthesized or identified compound (i.e., test compound) can beevaluated for its ability to reduce binding of the “radiolabelledcompound of Formula (Ia)” to the RUP3 receptor. Accordingly, the abilityto compete with the “radio-labelled compound of Formula (Ia)” orRadiolabelled RUP3 Ligand for the binding to the RUP3 receptor directlycorrelates to its binding affinity of the test compound to the RUP3receptor.

Assay Protocol for Determining Receptor Binding for RUP3:

A. RUP3 Receptor Preparation

293 cells (human kidney, ATCC), transiently transfected with 10 ug humanRUP3 receptor and 60 ul Lipofectamine (per 15-cm dish), were grown inthe dish for 24 hours (75% confluency) with a media change and removedwith 10 ml/dish of Hepes-EDTA buffer (20 mM Hepes+10 mM EDTA, pH 7.4).The cells were then centrifuged in a Beckman Coulter centrifuge for 20minutes, 17,000 rpm (JA-25.50 rotor). Subsequently, the pellet wasresuspended in 20 mM Hepes+1 mM EDTA, pH 7.4 and homogenized with a50-ml Dounce homogenizer and again centrifuged. After removing thesupernatant, the pellets were stored at −80° C., until used in bindingassay. When used in the assay, membranes were thawed on ice for 20minutes and then 10 nL of incubation buffer (20 mM Hepes, 1 mM MgCl₂,100 mM NaCl, pH 7.4) added. The membranes were then vortexed toresuspend the crude membrane pellet and homogenized with a BrinkmannPT-3100 Polytron homogenizer for 15 seconds at setting 6. Theconcentration of membrane protein was determined using the BRL Bradfordprotein assay.

B. Binding Assay

For total binding, a total volume of 50 ul of appropriately dilutedmembranes (diluted in assay buffer containing 50 mM Tris HCl (pH 7.4),10 mM MgCl₂, and 1 mM EDTA; 5-50 μg protein) is added to 96-wellpolyproylene microtiter plates followed by addition of 100 ul of assaybuffer and 50 μl of Radiolabelled RUP3 Ligand. For nonspecific binding,50 μl of assay buffer is added instead of 100 μl and an additional 50 μlof 10 μM cold RUP3 is added before 50 μl of Radiolabelled RUP3 Ligand isadded. Plates are then incubated at room temperature for 60-120 minutes.The binding reaction is terminated by filtering assay plates through aMicroplate Devices GF/C Unifilter filtration plate with a Brandell96-well plate harvestor followed by washing with cold 50 mM Tris HCl, pH7.4 containing 0.9% NaCl. Then, the bottom of the filtration plate aresealed, 50 μl of Optiphase Supermix is added to each well, the top ofthe plates are sealed, and plates are counted in a Trilux MicroBetascintillation counter. For compound competition studies, instead ofadding 100 μl of assay buffer, 100 μl of appropriately diluted testcompound is added to appropriate wells followed by addition of 50 ul ofRadiolabelled RUP3 Ligand.

C. Calculations

The test compounds are initially assayed at 1 and 0.1 μM and then at arange of concentrations chosen such that the middle dose would causeabout 50% inhibition of a Radio-RUP3 Ligand binding (i.e., IC₅₀).Specific binding in the absence of test compound (B_(O)) is thedifference of total binding (B_(T)) minus non-specific binding (NSB) andsimilarly specific binding (in the presence of test compound) (B) is thedifference of displacement binding (B_(D)) minus non-specific binding(NSB). IC₅₀ is determined from an inhibition response curve, logit-logplot of % B/B_(O) vs concentration of test compound.

K_(i) is calculated by the Cheng and Prustoff transformation:K _(i) =IC ₅₀/(1+[L]/K _(D))

where [L] is the concentration of a Radio-RUP3 Ligand used in the assayand K_(D) is the dissociation constant of a Radio-RUP3 Ligand determinedindependently under the same binding conditions.

CHEMISTRY EXAMPLES Syntheses of Compounds of The Present Invention

The compounds of the invention and their synthesis are furtherillustrated by the following examples. The following examples areprovided to further define the invention without, however, limiting theinvention to the particulas of these examples. The compounds describedherein, supra and infra, are named according to the CS Chem Draw UltraVersion 7.0.1. In certain instances common names are used and it isunderstood that these common names would be recognized by those skilledin the art.

Chemistry: Proton nuclear magnetic resonance (¹H NMR) spectra wererecorded on a Varian Mercury Vx400 equipped with a 4 nucleus autoswitchable probe and z-gradient or a Bruker Avance-400 equipped with aQNP (Quad Nucleus Probe) or a BBI (Broad Band Inverse) and z-gradient.Chemical shifts are given in parts per million (ppm) with the residualsolvent signal used as reference. NMR abbreviations are used as follows:s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, br=broad.Microwave irradiations were carried out using the Emyrs Synthesizer(Personal Chemistry). Thin-layer chromatography (TLC) was performed onsilica gel 60 F₂₅₄ (Merck), preparatory thin-layer chromatography (prepTLC) was preformed on PK6F silica gel 60 A 1 mm plates (Whatman), andcolumn chromatography was carried out on a silica gel column usingKieselgel 60, 0.063-0.200 mm (Merck). Evaporation was done in vacuo on aBuchi rotary evaporator. Celite 545 M was used during palladiumfiltrations.

LCMS specs: 1) PC: HPLC-pumps: LC-10AD VP, Shimadzu Inc.; HPLC systemcontroller: SCL-10A VP, Shimadzu Inc; UV-Detector: SPD-10A VP, ShimadzuInc; Autosampler: CTC HTS, PAL, Leap Scientific; Mass spectrometer: API150EX with Turbo Ion Spray source, AB/MDS Sciex; Software: Analyst 1.2.2) Mac: HPLC-pumps: LC-8A VP, Shimadzu Inc; HPLC system controller:SCL-10A VP, Shimadzu Inc. UV-Detector: SPD-10A VP, Shimadzu Inc;Autosampler: 215 Liquid Handler, Gilson Inc; Mass spectrometer: API150EX with Turbo Ion Spray source, AB/MDS Sciex Software: Masschrom1.5.2.

Example 9 Example 9.1 Preparation of4-[6-(2,5-difluoro-4-propoxy-phenylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound 74) Step A: Preparation of4-(6-chloro-5-methoxy-pyrimidin-4-yloxy)-piperidine-1-carboxylic acidisopropyl ester

To a solution of 4-hydroxy-piperidine-1-carboxylic acid isopropyl ester(3.15 g, 17 mmol) and 4,6-dichloro-5-methoxy-pyrimidine (3.00 mg, 17mmol) in 15 ml of THF, 1M potassium-t-butoxide in THF (18.4 ml, 18.4mmol) was added dropwise at 0° C. After 45 min, the crude mixture wasextracted with CH₂Cl₂ and brine. Organic phase was dried over MgSO₄,filtered, and concentrated. The residue was purified by columnchromatography on silica gel with hexane/ethyl acetate (3:1→1:1 v/v) toprovide 4-(6-chloro-5-methoxy-pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester as a solid (4.7 g, 85%). ¹HNMR (CDCl₃, 400 MHz) δ1.24-1.28 (d, 6H), 1.80-1.84 (m, 2H), 2.00-2.05 (m, 2H), 3.37-3.44 (m,2H), 3.77-3.81 (m, 2H), 3.91 (s, 3H), 4.92-4.95 (m, 1H), 5.38-5.40 (m,1H), 8.27 (s, 1H). Exact mass calculated for C₁₄H₂₀ClN₃O₄329.11, found330.1 (MH⁺).

Step B: Preparation of 2,5-difluoro-4-nitro-phenol

A solution of 2,5-difluorophenol (5 g, 38.4 mmol) in acetic acid (10 mL)was added slowly to a mixture of concentrated nitric acid (10 mL) andacetic acid (10 mL) cooled in an acetonitrile/dry ice bath in a mannerthat temperature did not exceed −18° C. After everything was added,solution was kept at −30° C. for 30 minutes, stirred at −13° C. for 30minutes, and then at 0° C. for 1 hour. Solution was transferred into aseparatory funnel, diluted with methylene chloride, and extracted threetimes with water. Organic phase was dried over magnesium sulfate,filtered, and concentrated. Residue was purified by columnchromatography on SiO₂ (hexane/acetyl acetate 1:1) to give2,5-difluoro-4-nitro-phenol as a yellow solid (1.74 g, 26%). ¹HNMR(MeOD, 400 MHz) δ 7.97-7.93 (m, 1H), 6.95-6.91 (m, 1H), 6.17 (s, 1H).

Step C: Preparation of 1,4-difluoro-2-nitro-5-propoxy-benzene

To a solution of 2,5-difluoro-4-nitro-phenol (1.71 g, 9.77 mmol) inacetonitrile (20 mL), potassium carbonate (2.7 g, 19.5 mmol) and1-iodopropane (1.14 mL, 11.7 mmol) were added. After stirring at 60° C.for 15 hours, mixture was concentrated and extracted with methylenechloride and 2M NaOH solution. Organic phases were dried over magnesiumsulfate, filtered, and concentrated to give1,4-difluoro-2-nitro-5-propoxy-benzene as a yellow solid (0.995 g, 47%).¹HNMR (CDCl₃, 400 MHz) δ 7.92-7.88 (m, 1H), 6.83-6.78 (m, 1H), 4.08-4.05(t, J=6.5 Hz, 2H), 1.95-1.86 (m, 2H), 1.10-1.06 (t, J=7.4 Hz, 2H).

Step D: Preparation of 2,5-difluoro-4-propoxy-phenylamine

To a solution of 1,4-difluoro-2-nitro-5-propoxy-benzene (0.99 g, 4.59mmol) in acetic acid (10 mL), zinc dust (1.5 g, 22.9 mmol) were added.After 30 minutes, more acetic acid (10 mL) and zinc dust were added (1.5g, 22.9 mmol). Zinc was filtered off, residue was concentrated andpurified by HPLC to give 2,5-difluoro-4-propoxy-phenylamine as a purplesolid (TFA salt, 401 mg, 29%). ¹HNMR (CDCl₃, 400 MHz) δ 6.99-7.87 (m,2H), 3.93-3.90 (t, J=6.4, 2H), 1.79-1.71 (m, 2H), 1.01-0.98 (t, J=7.4Hz, 2H). Exact mass calculated for C₉H₁₁F₂NO 187.08, found 188.1 (MH⁺).

Step E: Preparation of4-[6-(2,5-difluoro-4-propoxy-phenylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound 74)

A mixture of4-(6-chloro-5-methoxy-pyrimidin-4-yloxy)-piperidine-1-carboxylic acidisopropyl ester (528 mg, 1.6 mmol), palladium acetate (29.4 mg, 0.13mmol), biphenyl-2-yl-di-tert-butyl-phosphane (19.5 mg, 0.065 mmol),sodium tert-butoxide (315 mg, 3.28 mmol), and2,5-difluoro-4-propoxy-phenylamine (TFA salt, 395 mg, 1.31 mmol) in 15mL dioxane was heated under microwave irradiation at 120° C. After 2hours, more palladium acetate (29.4 mg, 0.13 mmol) was added and mixturewas heated under microwave irradiation at 120° C. for 18 hours. Mixturewas purified by HPLC to give4-[6-(2,5-difluoro-4-propoxy-phenylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound 74) as a tan solid (TFA salt, 217 mg,32%). ¹HNMR (MeOD, 400 MHz) δ 8.06-8.05 (d, J=2.0 Hz, 1H), 7.41-7.36 (m,1H), 7.09-7.04 (m, 1H), 5.41-5.39 (m, 1H), 4.87-4.81 (m, 1H), 4.01-3.98(t, J=6.4 Hz, 2H), 3.92 (s, 3H), 3.74-3.71 (m, 2H), 3.55-3.52 (m, 2H),2.00-1.97 (m, 2H), 1.81-1.77 (m, 4H), 1.21-1.19 (d, J=5.5 Hz, 6H),1.04-1.00 (t, 5.5 Hz, 3H). Exact mass calculated for C₂₃H₃₀F₂N₄O₅480.22, found 481.2 (MH⁺).

Example 9.2 Preparation of4-[6-(4-ethoxy-2,5-difluoro-phenylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound 75) Step A: Preparation of1-ethoxy-2,5-difluoro-4-nitro-benzene.

To a solution of 2,5-difluoro-4-nitro-phenol (4.86 g, 28.2 mmol) inacetonitrile (50 mL), potassium carbonate (4.7 g, 34 mmol) andbromoethane (4.21 mL, 56.4 mmol) were added. After stirring at 70° C.for 3.5 hours, iodoethane (2.73, 33.8 mmol) was added and mixture wasstirred at 80° C. After 20 hours, mixture was concentrated and extractedwith methylene chloride and 2M NaOH solution. Organic phases were driedover magnesium sulfate, filtered, and concentrated to give1-ethoxy-2,5-difluoro-4-nitro-benzene as a yellow solid (5.05 g, 88%).¹HNMR (CDCl₃, 400 MHz) δ 7.92-7.88 (m, 1H), 6.82-6.78 (m, 1H), 4.21-4.16(q, 1H), 4.13-4.07 (q, J=7.0 Hz, 2H), 1.54-1.51 (t, J=7.0 Hz, 3H).

Step B: Preparation of 4-ethoxy-2,5-difluoro-phenylamine.

A mixture of 1-ethoxy-2,5-difluoro-4-nitro-benzene (1.00 g, 4.92 mmol)and palladium on carbon (10%, 50% water, 307 mg) in ethanol (20 mL) wereshaken in a hydrogenator under H₂ atmosphere at 45 psi. After 30minutes, solids were filtered off, washed with ethanol, and filtrate wasconcentrated to give 4-ethoxy-2,5-difluoro-phenylamine as a red solid(835 mg, 98%). ¹HNMR (CDCl₃, 400 MHz) δ 6.72-6.67 (m, 1H), 6.58-6.53 (m,1H), 4.03-3.97 (q, J=7.0 Hz, 2H), 3.50 (s br, 2H), 1.41-1.37 (t, J=7.0Hz, 3H). Exact mass calculated for C₈H₉F₂NO 173.07, found 174.2 (MH⁺).

Step C: Preparation of4-[6-(4-ethoxy-2,5-difluoro-phenylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound 75)

A mixture of4-(6-chloro-5-methoxy-pyrimidin-4-yloxy)-piperidine-1-carboxylic acidisopropyl ester (6.71 g, 20.3 mmol), palladium acetate (460 mg, 2.05mmol), biphenyl-2-yl-di-tert-butyl-phosphane (77.0 mg, 0.26 mmol),sodium tert-butoxide (2.7 g, 28.1 mmol) and4-ethoxy-2,5-difluoro-phenylamine (3.26 g, 18.8 mmol) in 100 mL toluenewas heated under reflux for 17 hours. Mixture was purified by HPLC togive4-[6-(4-ethoxy-2,5-difluoro-phenylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound 75) as a tanned solid (TFA salt, 1.36 g,14%). ¹HNMR (CDCl₃, 400 MHz) δ 8.25 (s, 1H), 7.47-7.41 (m, 1H),6.81-6.76 (m, 1H), 5.52-5.48 (m, 1H), 4.98-4.88 (m, 1H), 4.13-4.07 (q,J=7.0 Hz, 2H), 3.84-3.76 (m, 2H), 3.68 (s, 3H), 3.40-3.33 (m, 2H),2.09-2.04 (m, 2H), 1.85-1.77 (m, 2H), 1.49-1.46 (t, J=7.0 Hz, 3H),1.10-1.09 (d, J=6.3 Hz, 6H). Exact mass calculated for C₂₂H₂₈F₂N₄O₅466.48, found 467.5 (MH⁺).

Example 9.3 Preparation of4-[2-(2,5-Difluoro-4-propoxy-phenylamino)-3-methoxy-pyridin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound 20) Step A: Preparation of2-chloro-4-nitro-pyridin-3-ol

A solution of 2-chloro-3-pyridinol (11.3 g, 87.2 mmol) in concentratedsulfuric acid (25 nL) was cooled in an ice-bath and a 1:1 mixture ofnitric acid and sulfuric acid (25 mL) was added slowly. After everythingwas added, solution was stirred at 0° C. for 1 hour and then at roomtemperature for another hour. Mixture was diluted with water andextracted with methylene chloride. Organic phases were dried overmagnesium sulfate, filtered, and concentrated. Residue was purified bycolumn chromatography on silica gel (ethyl acetate/hexane 2:1→3:1) togive 2-chloro-4-nitro-pyridin-3-ol as a tanned solid (3.58 g, 24%).¹HNMR (CDCl₃, 400 MHz) δ 10.5 (s, 2H), 8.14-8.13 (d, J=5.5 Hz, 1H),7.88-7.87 (d, J=5.5 Hz, 1H).

Step B: Preparation of 2-chloro-3-methoxy-4-nitro-pyridine

To a solution of 2-chloro-4-nitro-pyridin-3-ol (1.05 g, 6.02 mmol) inacetonitrile (45 mL) and methanol (5 mL), trimethylsilyldiazomethane (2Min hexane, 3.9 mL, 7.8 mmol) were added slowly. After 30 minutes,mixture was concentrated and residue was purified by columnchromatography on silica gel (hexane/ethyl acetate 5:1) to give2-chloro-3-methoxy-4-nitro-pyridine as a white solid (0.77 g, 68%).¹HNMR (CDCl₃, 400 MHz) δ 8.35-8.34 (d, J=5.1 Hz, 1H), 7.58-7.56 (d,J=5.2 Hz, 1H), 4.08 (s, 3H).

Step C: Preparation of4-(2-chloro-3-methoxy-pyridin-4-yloxy)-piperidine-1-carboxylic acidisopropyl ester

To a solution of 2-chloro-3-methoxy-4-nitro-pyridine (102.3 mg, 0.543mmol) and 4-hydroxy-piperidine-1-carboxylic acid isopropyl ester (110mg, 0.587 mmol) in dioxane (3 mL), sodium hydride (60% dispersion, 32mg, 0.8 mmol) were added. After stirring at 100° C. for 1 hour, mixturewas purified by HPLC to give4-(2-chloro-3-methoxy-pyridin-4-yloxy)-piperidine-1-carboxylic acidisopropyl ester as a white solid (42.0 mg, 24%). ¹HNMR (CDCl₃, 400 MHz)δ 8.16-8.15 (d, J=5.4 Hz, 1H), 6.92-6.90 (d, J=5.8 Hz), 4.97-4.91 (m,1H), 4.72-4.68 (m, 1H), 3.91 (s, 3H), 3.75-3.68 (m, 2H), 3.75-3.68 (m,2H), 3.55 (m, 2H), 2.02-1.85 (m, 4H), 1.27-1.26 (d, J=6.2 Hz, 6H). Exactmass calculated for C₁₅H₂₁ClN₂O₄ 328.12, found 329.2 (MH⁺).

Step D: Preparation of4-[2-(2,5-difluoro-4-propoxy-phenylamino)-3-methoxy-pyridin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound 20)

A mixture of4-(2-chloro-3-methoxy-pyridin-4-yloxy)-piperidine-1-carboxylic acidisopropyl ester (42 mg, 0.128 mmol), palladium acetate (30 mg, 0.13mmol),2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phospha-bicyclo[3.3.3]undecane (4.4μl, 0.013 mmol), sodium tert-butoxide (31 mg, 0.32 mmol), and2,5-difluoro-4-propoxy-phenylamine (30 mg, 0.13 mmol) in toluene (0.5mL) was heated under microwave irradiation at 120° C. for 1 hour.Mixture was purified by HPLC to give4-[2-(2,5-difluoro-4-propoxy-phenylamino)-3-methoxy-pyridin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound 20) as a tanned solid (TFA salt, 35.4 mg,47%). ¹HNMR (MeOD, 400 MHz) δ 7.52-7.50 (d, J=7.4 Hz, 1H), 7.23-7.18 (m,1H), 7.12-7.08 (m, 1H), 6.98-6.96 (m, 1H), 4.88-4.77 (m, 2H), 4.00-3.97(m, 2H), 3.90 (s, 3H), 3.72-3.67 (m, 2H), 3.41-3.37 (m, 2H), 2.00-1.96(m, 2H), 1.82-1.75 (m, 4H), 1.19-1.17 (d, J=6.1 Hz, 6H), 1.01-0.98 (t,J=7.4 Hz, 3H). Exact mass calculated for C₂₄H₃₁F₂N₃O₅ 479.22, found479.7 (MH⁺).

Example 9.4 Preparation of4-[6-(4-methanesulfonyl-2-methoxy-phenylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound 10) Step A: Preparation of4-[6-(4-bromo-2-methoxy-phenylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester

A mixture of4-(6-chloro-5-methoxy-pyrimidin-4-yloxy)-piperidine-1-carboxylic acidisopropyl ester (521 mg, 1.58 mmol), palladium acetate (75 mg, 0.33mmol), biphenyl-2-yl-di-tert-butyl-phosphane (51 mg, 0.17 mmol), sodiumtert-butoxide (380 mg, 3.95 mmol), and 4-bromo-2-methoxy-phenylamine(HCl salt, 377 mg, 1.58 mmol) in 15 mL dioxane was heated undermicrowave irradiation at 120° C. After 3 hours, mixture was purified byHPLC to give4-[6-(4-bromo-2-methoxy-phenylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester as a tanned solid (TFA salt, 124 mg, 13%). ¹HNMR(MeOD, 400 MHz) δ 8.05-8.04 (d, J=2.2 Hz, 1H), 7.93-7.91 (d, J=8.5 Hz,1H), 7.21-7.20 (d, J=2.0 Hz, 1H), 7.12-7.09 (m, 1H), 5.37-5.34 (m, 1H),4.89-4.79 (m, 1H), 3.94 (s, 3H), 3.86 (s, 3H), 3.74-3.70 (m, 2H),3.42-3.38 (m, 2H), 2.01-1.98 (m, 2H), 1.78-1.74 (m, 2H), 1.22-1.21 (d,J=6.2 Hz, 6H). Exact mass calculated for C₂₁H₂₇BrN₄O₅ 494.12, found495.1 (MH⁺).

Step B: Preparation of4-[6-(4-methanesulfonyl-2-methoxy-phenylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound 10)

A mixture of4-[6-(4-bromo-2-methoxy-phenylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (TFA salt, 112 mg, 0.184 mmol), sodiummethansulfinate (51 mg, 0.425 mmol), copper (I) trifluoromethanesulfonate benzene complex (92 mg, 0.16 mmol), andN,N-dimethylethylendiamine (60 μl, 0.56 mmol) in DMSO (4.5 mL) wereheated under microwave irradiation at 160° C. for 30 minutes. Mixturewas purified by HPLC to give4-[6-(4-methanesulfonyl-2-methoxy-phenylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound 10) as a white solid (TFA salt, 45.7 mg,41%). ¹HNMR (MeOD, 400 MHz) δ 8.75-8.73 (m, 1H), 8.13-8.12 (d, 2.2 Hz,1H), 7.53-7.47 (m, 2H), 5.37-5.33 (m, 1H), 4.85-4.80 (m, 1H), 4.00 (s,3H), 3.91 (s, 3H), 3.75-3.70 (m, 2H), 3.42-3.37 (m, 2H), 3.08 (s, 3H),2.02-1.97 (m, 2H), 1.78-1.73 (m, 2H), 1.22-1.21 (d, J=6.2 Hz, 6H). Exactmass calculated for C₂₂H₃₀N₄O₇S 494.18, found 495.5 (MH⁺).

Example 9.5 Preparation of4-[6-(2-fluoro-4-methanesulfonyl-phenylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound 24)

A mixture of4-(6-chloro-5-methoxy-pyrimidin-4-yloxy)-piperidine-1-carboxylic acidisopropyl ester (2.494 g, 7.56 mmol),2-fluoro-4-(methylsulfonyl)-aniline (1.4315 g, 7.56 mmol), palladiumacetate (169.9 mg, 0.756 mmol),2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phospha-bicyclo[3.3.3]undecane(26.8 μL, 0.0756 mmol) and sodium tert-butoxide (1.475 g, 15.3 mmol) indioxane (30 mL) was heated under microwave irradiation at 120° C. for 2hours. The crude mixture was purified by HPLC and recrystalized withEtOH to provide compound4-[6-(2-fluoro-4-methanesulfonyl-phenylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound 24) as a solid (TFA salt, 513 mg, 11.3%).¹HNMR (DMSO-d₆, 400 MHz) δ 1.19-1.20 (d, 6H), 1.65-1.70 (m, 2H),1.94-1.99 (m, 2H), 3.26 (s, 3H), 3.31-3.35 (m, 2H), 3.63-3.69 (m, 2H),3.85 (s, 3H), 4.77-4.80 (m, 1H), 5.29-5.31 (m, 1H), 7.73-7.75(m, 1H),7.80-7.83 (m, 1H), 8.06-8.11 (m, 2H), 8.79 (s, 1H). Exact masscalculated for C₂₁H₂₇FN₄O₆S 482.16, found 483.3 (MH⁺).

Example 9.6 Preparation of4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound 76) Step A: Preparation of4-(6-chloro-5-methoxy-pyrimidin-4-yloxy)-piperidine-1-carboxylic acidisopropyl ester

A mixture of4-(6-chloro-5-methoxy-pyrimidin-4-yloxy)-piperidine-1-carboxylic acidisopropyl ester (2.19 g, 6.7 mmol), potassium carbonate (1.84 g, 13.3mmol), and 4-bromo-2-fluorophenol (1.65 g, 8.65 mmol) in 32 ml DMA washeated at 160° C. for 5 hours. The mixture was extracted with AcOEt andbrine. Organic phase was dried over MgSO₄, filtered and concentrated.The residue was purified by HPLC to give4-[6-(4-bromo-2-fluoro-phenoxy)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester as an oil (1.12 g, 35%). Exact mass calculated forC₂₀H₂₃BrFN₃O₅ 483.08, found 484.4 (MH⁺).

Step B: Preparation of4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound 76)

A mixture of4-[6-(4-bromo-2-fluoro-phenoxy)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (0.543 g, 1.21 mmol), sodium methane sulfinate(774.2 mg, 7.58 mmol), and N,N′-dimethyl-ethylene diamine (50.31 μl,0.44 mmol) and copper (I) trifluoromethane sulfonate benzene complex(384.9 mg, 0.759 mmol) in 20 mL DMSO was heated in microwave for 7minutes at 120° C. The mixture was purified by HPLC to give compound4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound 76) as an oil (242.7 mg, 42%). ¹HNMR(DMSO-d₆, 400 MHz) δ 1.19-1.21 (d, 6H), 1.68-1.72 (m, 2H), 1.97-2.02 (m,2H), 3.30-3.33 (m, 2H), 3.33 (s, 3H), 3.65-3.71 (m, 2H), 3.90 (s, 3H),4.78-4.81 (m, 1H), 5.28-5.37(m, 1H), 7.69-7.73 (m, 1H), 7.84-7.87 (m,1H), 8.00-8.03 (m, 1H), 8.16 (s, 1H). Exact mass calculated forC₂₁H₂₆FN₃O₇S 483.15, found 484.2 (MH⁺).

Example 9.7 Preparation of4-[2-(2-fluoro-4-methanesulfonyl-phenylamino)-3-methoxy-pyridin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound 77)

A mixture of compound4-(2-chloro-3-methoxy-pyridin-4-yloxy)-piperidine-1-carboxylic acidisopropyl ester (TFA salt, 57 mg, 0.13 mmol),2-fluoro-4-(methylsulfonyl)-aniline (49 mg, 0.26 mmol), palladiumacetate (29 mg, 0.13 mmol),2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phospha-bicyclo[3.3.3]undecane(11.5 μl, 0.033 mmol), and sodium tert-butoxide (24 mg, 0.25 mmol) in 2mL of dioxane was purged with argon and heated under microwaveirradiation at 120° C. for 2 hours. The crude mixture was purified byHPLC to provide4-[2-(2-fluoro-4-methanesulfonyl-phenylamino)-3-methoxy-pyridin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound 77) as an oil (TFA salt, 50 mg, 65%).¹HNMR (CDCl₃, 400 MHz) δ 1.26-1.28 (d, 6H), 1.89-1.91 (m, 2H), 2.02-2.05(m, 2H), 3.08 (s, 3H), 3.49-3.54 (m, 2H), 3.69 (s, 3H), 3.71-3.77 (m,2H), 4.78-4.79 (m, 1H), 4.93-4.96(m, 1H), 6.76-6.77 (m, 1H), 7.61-7.63(m, 1H), 7.69-7.73 (m, 2H), 7.91-7.92 (m, 1H) 9.70 (s, 1H). Exact masscalculated for C₂₂H₂₈FN₃O₆S 481.17, found 482.3 (MH⁺).

Example 9.8 Preparation of4-{5-methoxy-6-[6-(2-methoxy-ethylamino)-2-methyl-pyridin-3-ylamino]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester (Compound 31) Step A: Preparation of(2-methoxy-ethyl)-(6-methyl-5-nitro-pyridin-2-yl)-amine

A mixture of 2-fluoro-5-nitro-6-picoline (656 mg, 4.2 mmol) and2-methoxyethylamine (365 μl, 4.2 mmol) was stirred at 0° C. After 10min, crude (2-methoxy-ethyl)-(6-methyl-5-nitro-pyridin-2-yl)-amine (957mg) was obtained as a solid. ¹HNMR (CDCl₃, 400 MHz) δ 2.77 (s, 3H), 2.85(s, 2H), 3.40 (s, 3H), 3.57-3.60 (m, 2H), 5.51 (s br, 1H), 6.26-6.29 (m,1H), 8.18-8.20 (m, 1H). Exact mass calculated for C₉H₁₃N₃O₃ 211.10,found 212.2 (MH⁺).

Step B: Preparation ofN2-(2-methoxy-ethyl)-6-methyl-pyridine-2,5-diamine

To a suspension of(2-methoxy-ethyl)-(6-methyl-5-nitro-pyridin-2-yl)-amine (421 mg, 2 mmol)and 5 ml of acetic acid, Zn dust (781 mg, 12 mmol) was added at 0° C.The mixture was stirred at 60° C. for 1 hour. Zn dust was filteredthrough celite and the residue was purified by HPLC to provideN²-(2-Methoxy-ethyl)-6-methyl-pyridine-2,5-diamine as an oil (140 mg,39%). Exact mass calculated for C₉H₁₅N₃O 181.12, found 182.2 (MH⁺).

Step C: Preparation of4-{5-methoxy-6-[6-(2-methoxy-ethylamino)-2-methyl-pyridin-3-ylamino]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester (Compound 31)

Compound 31 was obtained in a similar manner as described in Example 9.5as an oil (HCl salt, 170 mg, 88%). ¹HNMR (MeOD-d₄, 400 MHz) δ 1.16-1.18(d, 6H), 1.71-1.74 (m, 2H), 1.94-1.98 (m, 2H), 2.36 (s, 3H), 3.21-3.22(m, 6H), 3.33 (s, 3H), 3.33-3.36 (m, 2H), 3.66-3.70 (m, 2H), 3.88 (s,3H), 4.80-4.82 (m, 1H), 5.34-5.35 (m, 1H), 6.95-6.97 (m, 1H), 7.73-7.76(m, 1H), 8.00 (s, 1H). Exact mass calculated for C₂₃H₃₄N₆O₅ 474.26,found 475.2 (MH⁺).

Example 9.9 Preparation of4-{6-[6-(2-hydroxy-ethylamino)-2-methyl-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester (Compound 78)

To a solution of4-{5-methoxy-6-[6-(2-methoxy-ethylamino)-2-methyl-pyridin-3-ylamino]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester (HCl salt, 101 mg, 0.2 mmol) in 10 mL of CH₂Cl₂,iodotrimethylsilane (142 μl, 1 mmol) was added at room temperature. Themixture was stirred at the same temperature. After 2 hr, the mixture waspurified by HPLC and converted to HCl salt by adding 2 mL of 4M HCl indioxane solution and concentrated to give4-{6-[6-(2-hydroxy-ethylamino)-2-methyl-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester (Compound 78) (HCl salt, 37 mg, 37%). ¹HNMR(CD₃CN-d₃, 400 MHz) δ 1.12-1.14 (d, 6H), 1.66-1.68 (m, 2H), 1.84-1.89(m, 2H), 2.35 (s, 3H), 3.27-3.32 (m, 2H), 3.41 (s, 2H), 3.61 (s, 4H),3.82 (s, 3H), 4.72-4.78 (m, 1H), 5.28 (m, 1H), 6.88-6.90 (m, 1H),6.69-7.71 (m, 1H), 7.99 (s, 1H) 8.18 (s br, 1H), 8.42 (s br, 1H). Exactmass calculated for C₂₂H₃₂N₆O₅ 460.24, found 461.5 (MH⁺).

Example 9.104-{6-[6-(2-Hydroxy-ethylsulfanyl)-2-methyl-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester (Compound 79) Step A: Preparation of2-(6-methyl-5-nitro-pyridin-2-ylsulfanyl)-ethanol

To a solution of 2-fluoro-5-nitro-6-picoline (5.0 g, 32 mmol) and2-mercaptoethanol (4.5 ml, 64 mmol), KOH (2 g, 36 mmol) was added at 0°C. The mixture was stirred at the same temperature for 15 minutes. Thecrude mixture was extracted with AcOEt and brine. Organic phase wasdried over MgSO₄, filtered, and concentrated to provide the crude2-(6-methyl-5-nitro-pyridin-2-ylsulfanyl)-ethanol as an oil (7.238 g).¹HNMR (DMSO-d₄, 400 MHz) δ 2.75 (s, 3H), 3.30-3.33 (m, 2H), 3.63-3.67(m, 2H), 4.65-4.68 (m, 1H), 7.40-7.43 (m, 1H), 8.24-8.26 (m, 1H). Exactmass calculated for C₈H₁₀N₂O₃S 214.04, found 215.1 (MH⁺).

Step B: Preparation of2-(5-amino-6-methyl-pyridin-2-ylsulfanyl)-ethanol.

To a suspension of 2-(6-methyl-5-nitro-pyridin-2-ylsulfanyl)-ethanol(323 mg, 1.5 mmol) and 7 ml of acetic acid, zinc dust (220 mg, 3.4 mmol)was added at 0° C. The mixture was stirred at room temperature for 2 hr.Zinc dust was filtered through celite and the residue was purified byHPLC to provide 2-(5-amino-6-methyl-pyridin-2-ylsulfanyl)-ethanol as anoil (93 mg, 33%). ¹HNMR (DMSO-d₄, 400 MHz) δ 1.91 (s, 1H), 2.38 (s, 3H),2.50-2.51 (m, 2H), 3.12-3.15 (m, 2H), 3.57-3.61 (m, 2H), 7.26-7.28 (m,1H), 734-7.36 (m, 1H). Exact mass calculated for C₈H₁₂N₂OS 184.07, found184.9 (MH⁺).

Step C: Preparation of4-{6-[6-(2-hydroxy-ethylsulfanyl)-2-methyl-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester (Compound 79)

4-{6-[6-(2-Hydroxy-ethylsulfanyl)-2-methyl-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester (Compound 79) was obtained in a similar manner asdescribed in Example 9.5 as a solid (TFA salt, 30.6 mg, 10%). ¹HNMR(CDCl₃, 400 MHz) δ 1.25-1.27 (d, 6H), 1.75-1.83 (m, 2H), 1.97-2.02 (m,2H), 2.57 (s, 3H), 3.34-3.39 (m, 2H), 3.41-3.46 (m, 2H), 3.76 (s, 3H),3.78-3.82 (m, 2H), 4.57-4.60 (m, 2H), 4.90-4.96 (m, 1H), 5.29-5.33 (m,1H), 7.40-7.42 (m, 1H), 7.55-7.57 (m, 1H), 8.07 (s, 1H). Exact masscalculated for C₂₂H₃₁N₅O₅S 477.2, found 477.7 (MH⁺).

Example 9.11 Preparation of4-{6-[6-(2-hydroxy-ethylsulfanyl)-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester (Compound 80) Step A: Preparation of2-(5-nitro-pyridin-2-ylsulfanyl)-ethanol

2-(5-Nitro-pyridin-2-ylsulfanyl)-ethanol was obtained in a similarmanner as described in Example 9.9/Step A as crude product (835 mg).Exact mass calculated for C₇H₈N₂O₃S 200.03, found 201.2 (MH⁺).

Step B: Preparation of 2-(5-amino-pyridin-2-ylsulfanyl)-ethanol

2-(5-Amino-pyridin-2-ylsulfanyl)-ethanol was obtained in a similarmanner as described in Example 9.9/Step B as an oil (277 mg, 39%). ¹HNMR(CDCl₃, 400 MHz) δ 3.20-3.22 (m, 2H), 3.92-3.95 (m, 2H), 4.07 (s br,3H), 6.91-6.93 (m, 1H), 7.13-7.15 (m, 1H), 7.92-7.93 (s, 1H). Exact masscalculated for C₇H₁₀N₂OS 170.05, found 171.1 (MH⁺).

Step C: Preparation of4-{6-[6-(2-hydroxy-ethylsulfanyl)-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester (Compound 80)

4-{6-[6-(2-Hydroxy-ethylsulfanyl)-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester was obtained in a similar manner as described inExample 9.5 as a solid (HCl salt, 25 mg, 15.5%). ¹HNMR (CDCl₃, 400 MHz)δ 1.26-1.27 (d, 6H), 1.83-1.84 (m, 2H), 2.03-2.04 (m, 2H), 3.40-3.45 (m,2H), 3.46-3.51 (m, 2H), 3.64-3.644 (m, 1H), 3.75-3.79 (m, 2H), 4.00 (s,3H), 4.08 (m, 2H), 4.92-4.96 (m, 1H), 5.39 (s br, 1H), 7.58-7.64 (m,1H), 8.17-8.20 (m, 1H), 8.88 (s br, 1H), 9.49 (s br, 1H). Exact masscalculated for C₂₁H₂₉NSO₅S 463.19, found 464.4 (MH⁺).

Example 9.12 Preparation of4-{6-[6-(2-methanesulfonyl-ethylamino)-2-methyl-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester (Compound 81) Step A: Preparation of2-(5-nitro-pyridin-2-ylsulfanyl)-ethanol.

To a solution of 2-fluoro-5-nitro-6-picoline (300.3 mg, 1.92 mmol) and2-aminoethylmethylsulfone hydrochloride (HCl salt, 309 mg, 1.93 mmol) in5 ml of THF, K₂CO₃ (798 mg, 5.77 mmol) was added at room temperature.The mixture was stirred at 60° C. for 100 hours. The crude mixture waspurified by HPLC to provide(2-methanesulfonyl-ethyl)-(6-methyl-5-nitro-pyridin-2-yl)-amine as anoil (TFA salt, 562 mg, 78%). Exact mass calculated for C₉H₁₃N₃O₄S259.06, found 259.8 (MH⁺).

Step B: Preparation ofN2-(2-methanesulfonyl-ethyl)-6-methyl-pyridine-2,5-diamine

N²-(2-Methanesulfonyl-ethyl)-6-methyl-pyridine-2,5-diamine was obtainedin a similar manner as described in Example 9.9/Step B as an oil (184mg, 56%). Exact mass calculated for C₉H₁₅N₃O₂S 229.09, found 230.3(MH⁺).

Step C: Preparation of4-{6-[6-(2-methanesulfonyl-ethylamino)-2-methyl-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester (Compound 81)

4-{6-[6-(2-Methanesulfonyl-ethylamino)-2-methyl-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester was obtained in a similar manner as described inExample 9.5 as an oil (TFA salt, 41 mg, 16%). ¹HNMR (CDCl₃, 400 MHz) δ1.25-1.29 (d, 6H), 1.80-1.82 (m, 2H), 2.01-2.02 (m, 2H), 2.48 (s, 3H),3.02 (s, 3H), 3.37-3.41 (m, 2H), 3.42-3.47 (m, 2H), 3.78-3.79 (m, 2H),3.83-3.84 (m, 2H), 3.94 (s, 3H), 4.92-4.95 (m, 1H), 5.35-5.37 (m, 1H),6.75-6.80 (m, 1H), 8.01 (s, 1H), 8.05-8.08 (m, 1H). Exact masscalculated for C₂₃H₃₄N₆O₆S 522.23, found 523.5 (MH⁺).

Example 9.13 Preparation of4-{2-[2-fluoro-4-(2-methoxy-ethoxy)-phenylamino]-3-methoxy-pyridin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester (Compound 82) Step A: Preparation of2-fluoro-4-(2-methoxy-ethoxy)-phenylamine

A mixture of 2-fluoro-4-iodo-phenylamine (2.3672 g, 10 mmol),2-methoxyethanol (13 ml, 164 mmol), copper(I)iodide (190 mg, 1 mmol),1,10-phenanthridine (360 mg, 2 mmol), and cesium carbonate (4.55 g mg,14 mmol) was sealed and heated at 110° C. After 17 hours, the crudemixture was extracted with CH₂Cl₂ and brine. Organic phase was driedover MgSO₄, filtered, and concentrated. The residue was purified bycolumn chromatography on silica gel with hexane/ethyl acetate (1:1 v/v)twice to give 2-fluoro-4-(2-methoxy-ethoxy)-phenylamine as an oil (761mg, 41%). Exact mass calculated for C₉H₁₂FNO₂ 185.09, found 186.0 (MH⁺).

Step B: Preparation of4-{2-[2-fluoro-4-(2-methoxy-ethoxy)-phenylamino]-3-methoxy-pyridin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester

4-{2-[2-Fluoro-4-(2-methoxy-ethoxy)-phenylamino]-3-methoxy-pyridin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester was obtained in a similar manner as described inExample 9.7 as an oil (TFA salt, 173 mg, 84%). ¹HNMR (CDCl₃, 500 MHz) δ1.25-1.28 (d, 6H), 1.88-1.90 (m, 2H), 2.02 (s, 1H), 2.04-2.05 (m, 2H),3.48 (s, 3H), 3.49-3.54 (m, 2H), 3.73-3.76 (m, 2H), 3.77-3.80 (m, 2H),3.93 (s, 3H), 4.11-4.13 (m, 2H), 4.77-4.78 (m, 1H), 4.94-4.96 (m, 1H),6.64-6.65 (m, 1H), 6.77-6.80 (m, 2H) 7.57 (s, 1H), 7.70-7.71 (m, 1H).Exact mass calculated for C₂₄H₃₂FN₃O₆ 477.23, found 478.3 (MH⁺).

Example 9.14 Preparation of4-[6-(6-dimethylcarbamoylmethyl-2-methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound 47) Step A: Preparation of4-[6-(6-bromo-2-methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester

A mixture of4-(6-chloro-5-methoxy-pyrimidin-4-yloxy)-piperidine-1-carboxylic acidisopropyl ester (3.3 g, 10.0 mmol), 6-bromo-2-methyl-pyridin-3-ylamine(1.88 g, 10.0 mmol), palladium acetate (118 mg, 0.53 mmol),2-(di-t-butylphosphino) biphenyl (157 mg, 0.53 mmol) and LiN(TMS)₂ (1Min THF, 15 mL, 15 mmol) in 75 mL of dioxane was stirred under reflux.After 4.5 h, more palladium acetate (111 mg, 0.50 mmol) was added andmixture was stirred under reflux for another hour and then at roomtemperature for 3 days. The mixture was concentrated and residue wasextracted with brine and AcOEt. Organic phases were dried over MgSO₄,filtered, and concentrated. The residue was purified by columnchromatography (hexane/AcOEt 2:1→1:1) to give4-[6-(6-bromo-2-methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester as a solid (2.09 g, 44%). ¹HNMR (CDCl₃, 400 MHz) δ1.27-1.28 (d, 6H), 1.84-1.87 (m, 2H), 2.02-2.08 (m, 2H), 2.58 (s, 3H),3.40-3.47 (m, 2H), 3.73 (s, 3H), 3.77-3.82 (m, 2H), 4.93-4.97 (m, 1H),5.41-5.43 (m, 1H), 7.44-7.46 (m, 1H), 7.91-7.93 (m, 1H), 8.24 (s, 1H),8.70 (s br, 1H). Exact mass calculated for C₂₀H₂₆BrN₅O₄ 479.12, found482.0 (MH⁺).

Step B: Preparation of4-{6-[(6-bromo-2-methyl-pyridin-3-yl)-tert-butoxycarbonyl-amino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester

To a solution of4-[6-(6-bromo-2-methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester in 2 mL THF, Boc anhydride (62 mg, 0.28 mmol) andN,N-dimethylpyridin-4-amine (27 mg, 0.22 mmol) were added. Afterstirring for 30 min at room temperature, mixture was purified by columnchromatography (hexane/AcOEt 2:1) to give4-{6-[(6-bromo-2-methyl-pyridin-3-yl)-tert-butoxycarbonyl-amino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester as a white solid (118 mg, 92%). ¹HNMR (CDCl₃, 400MHz) δ 1.25-1.27 (d, J=6.2 Hz, 6H), 1.42 (s, 9H), 1.79-1.84 (m, 2H),1.99-2.05 (m, 2H), 2.52 (s, 3H), 3.39-3.47 (m, 2H), 3.71-3.77 (m, 2H),3.90 (s, 3H), 4.90-4.97 (m, 1H), 5.37-5.42 (m, 1H), 7.30-7.32 (d, J=8.3Hz, 1H), 7.41-7.43 (d, J=8.3 Hz, 1H), 8.24 (s, 1H). Exact masscalculated for C₂₅H₃₄BrN₅O₆ 579.17, found 580.1 (MH⁺).

Step C: Preparation of4-[6-(6-carboxymethyl-2-methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester

A mixture of4-{6-[(6-bromo-2-methyl-pyridin-3-yl)-tert-butoxycarbonyl-amino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester (1.5 g, 2.58 mmol), 2-tert-butoxy-2-oxoethylzincchloride (0.5 M in Et₂O, 20 mL, 10 mmol), and palladium[tetrakis(triphenylphosphine)] (304 mg, 0.263 mmol) were stirred underreflux. After 22 h, mixture was cooled in an ice water bath and ca. 5 mL4M HCl in dioxane was added. After 1 h, mixture was concentrated andresidue was extracted with 2M HCl and methylene chloride. The combinedorganic phases were concentrated and residue was purified by HPLC togive4-[6-(6-carboxymethyl-2-methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester as a white solid (TFA salt, 525 mg, 35%). ¹HNMR(MeOH-d₄, 400 MHz) δ 1.06-1.07 (d, J=6.2 Hz, 6H), 1.72-1.78 (m, 2H),2.00-2.05 (m, 2H), 2.78 (s, 3H), 3.37-3.43 (m, 2H), 3.70-3.75 (m, 2H),3.92 (s, 3H), 4.08 (s, 2H), 4.81-4.86 (m, 1H), 5.34-5.39 (m, 1H),7.76-7.78 (d, J=8.5 Hz, 1H), 7.98 (s, 1H), 8.65-8.67 (d, J=8.5 Hz, 1H).Exact mass calculated for C₂₂H₂₉BrN₅O₆ 459.21, found 460.5 (MH⁺).

Step D: Preparation of4-[6-(6-dimethylcarbamoylmethyl-2-methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound 47)

To a solution of4-[6-(6-carboxymethyl-2-methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (74 mg, 0.129 mmol), triethylamine (89.9 μl, 0.645mmol), and HATU (196 mg, 0.516 mmol) in 4 mL THF/DMF 1:1, diethylamine(2M in THF, 323 μl, 0.645 mmol) was added. After stirring for 10 min atroom temperature, mixture was purified by HPLC to give4-[6-(6-dimethylcarbamoylmethyl-2-methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester as a white solid (TFA salt, 45.6 mg, 68%). ¹HNMR(DMSO-d₆, 400 MHz) δ 1.19-1.21 (d, J=6.3 Hz, 6H), 1.65-1.70 (m, 2H),1.92-1.97 (m, 2H), 2.65 (s, 3H), 2.89 (s, 3H), 3.11 (s, 3H), 3.30-3.35(m, 2H), 3.64-3.69 (m, 2H), 3.85 (s, 3H), 4.26 (s, 2H), 4.76-4.81 (m,1H), 5.26-5.31 (m, 1H), 7.70-7.72 (d, J=8.5 Hz, 1H), 8.03 (s, 1H),8.44-8.46 (d, J=8.5 Hz, 1H), 9.09 (s, 1H). Exact mass calculated forC₂₄H₃₄N₆O₅ 486.26, found 487.3 (MH⁺).

Example 9.15 Preparation of4-{6-[6-(2-hydroxy-ethyl)-2-methyl-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester (Compound 27)

A solution of4-[6-(6-carboxymethyl-2-methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (TFA salt, 582 mg, 1.01 mmol) in 4 mL THF wascooled in an ice-water bath and lithium aluminum hydride (ca 190 mg, 5mmol) was added in small portions. After 2 h, mixture was quenched withice-water; solids were filtered off, and washed with THF. Filtrate wasconcentrated and purified by HPLC. Fractions containing product werepartly concentrated and residue was extracted with 1M NaOH and methylenechloride. Organic phases were dried over MgSO₄, filtered, andconcentrated to give4-{6-[6-(2-hydroxy-ethyl)-2-methyl-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester as a white solid (85.0 mg, 19%). ¹HNMR (CDCl₃, 400MHz) δ 1.25-1.27 (d, J=6.2 Hz, 6H), 1.80-1.86 (m, 2H), 2.00-2.05 (m,2H), 2.72 (s, 3H), 3.16-3.19 (t, J=5.6 Hz, 2H), 3.38-3.44 (m, 2H),3.76-3.82 (m, 2H), 3.96-3.99 (t, J=5.6 Hz, 2H), 4.00 (s, 3H), 4.91-4.97(m, 1H), 5.37-5.41 (m, 1H), 5.30 (s, 1H), 5.37-5.41 (m, 1H), 7.03 (s,1H), 7.36-7.38 (d, J=8.5 Hz, 1H), 8.13 (s, 1H), 8.85 (s, 1H). Exact masscalculated for C₂₂H₃₁N₅O₅ 445.23, found 446.1 (MH⁺).

Example 9.16 Preparation of4-{5-methoxy-6-[2-methyl-6-(2-methylsulfanyl-ethyl)-pyridin-3-ylamino]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester

To an ice-cooled solution of4-{6-[6-(2-hydroxy-ethyl)-2-methyl-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester (40.2 mg, 90.2 μmol) and triphenylphosphine (31 mg,118 μmol) in 2 mL methylene chloride, perbromomethane (77.0 mg, 232μmol) were added and solution was stirred at room temperature. After 18h, the mixture was concentrated, re-dissolved in 1.5 mL MeOH, and addedto a well stirred mixture of sodium hydroxide (120 mg, 3.0 mmol) and2-methyl-2-thiopseudourea sulfate (208 mg, 0.70 mmol) in 2 mL MeOH.After stirring at room temperature for 17 h, mixture was concentratedand extracted with water and methylene chloride. Organic phases wereconcentrated and purified by HPLC to give4-{5-methoxy-6-[2-methyl-6-(2-methylsulfanyl-ethyl)-pyridin-3-ylamino]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester (TFA salt, 10.0 mg, 19%) as a white solid. ¹HNMR(MeOH-d₄, 400 MHz) δ 1.21-1.23 (d, J=6.2 Hz, 6H), 1.72-1.78 (m, 2H),1.94-2.01 (m, 2H), 2.12 (s, 3H), 2.65 (s, 3H), 2.90-2.93 (t, J=7.2 Hz,2H), 3.24-3.27 (t, J=7.2 Hz, 2H), 3.39-3.46 (m, 2H), 3.69-3.76 (m, 2H),3.91 (s, 3H), 4.80-4.86 (m, 2H), 5.32-5.38 (m, 1H), 7.75-7.77 (d, J=8.6Hz, 1H), 7.96 (s, 1H), 8.57-5.59 (d, J=8.6 Hz, 1H). Exact masscalculated for C₂₃H₃₃N₅O₄S 475.23, found 476.2 (MH⁺).

Example 9.17 Preparation of4-{6-[6-(2-methanesulfonyl-ethyl)-2-methyl-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester (Compound 30)

To a solution of4-{5-methoxy-6-[2-methyl-6-(2-methylsulfanyl-ethyl)-pyridin-3-ylamino]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester (8.6 mg, 15 μmol) in 2 mL methylene chloride, MCPBA(ca. 77% pure, 7.1 mg, ca. 32 μmol) was added and stirred at roomtemperature. After 3 h, solution was concentrated and residue waspurified by HPLC to give4-{6-[6-(2-methanesulfonyl-ethyl)-2-methyl-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester (TFA salt, 9.1 mg, 47%). ¹HNMR (MeOH-d₄, 400 MHz) δ1.24-1.25 (d, J=6.2 Hz, 6H), 1.73-1.79 (m, 2H), 1.99-2.06 (m, 2H), 2.64(s, 3H), 3.15 (s, 3H), 3.40-3.46 (m, 2H), 3.48-3.51 (t, J=7.9 Hz, 2H),3.64-3.67 (t, J=7.9 Hz, 2H), 3.74-3.80 (m, 2H), 3.94 (s, 3H), 4.82-4.88(m, 1H), 3.35-3.40 (m, 1H), 7.78-7.80 (d, J=8.6, 1H), 7.99 (s, 1H),8.59-8.60 (d, J=8.6, 1H). Exact mass calculated for C₂₃H₃₃NSO₆S 507.22,found 508.5 (MH⁺).

Example 9.18 Preparation of4-[6-(2,6-dimethyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound 83)

A mixture of4-(6-chloro-5-methoxy-pyrimidin-4-yloxy)-piperidine-1-carboxylic acidisopropyl ester (1.52 g, 4.60 mmol), 2,6-dimethylpyridin-3-amine (0.562g, 4.60 mmol), palladium acetate (0.0584 g, 0.260 mmol), and sodium2-methylpropan-2-olate (0.663 g, 6.90 mmol) in 50 mL dioxane was stirredunder reflux for 18 h. Mixture was concentrated and extracted with brineand CH₂Cl₂. Organic phases were dried over MgSO₄, filtered, andconcentrated. Residue was purified by column chromatography(AcOEt/hexane 5:1→AcOEt→AcOEt/MeOH 10:1). Fractions containing pureproduct were concentrated, residue was treated with 4M HCl in dioxane,and concentrated to give4-[6-(2,6-dimethyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester as a white (0.285 g, 15%). Fractions containingproduct contaminated with 2,6-dimethylpyridin-3-amine was concentratedto give 0.30 g of ca 80% pure product. ¹HNMR (CDCl₃, 400 MHz) δ1.24-1.25 (d, J=6.2 Hz, 6H), 1.78-1.84 (m, 2H), 2.00-2.05 (m, 2H), 2.52(2s, 6H), 3.37-3.44 (m, 2H), 3.76-3.81 (m, 2H), 4.03 (s, 3H), 4.91-4.97(m, 1H), 5.33-5.38 (m, 1H), 6.81 (s, 1H), 7.04-7.06 (d, J=8.2 Hz, 1H),8.09 (s, 1H), 8.11-8.13 (d, J=8.2 Hz, 1H). Exact mass calculated forC₂₁H₂₉N₅O₄ 415.22, found 416.5 (MH⁺).

Example 9.19 Preparation of4-[6-(6-methanesulfonyl-2-methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound 84)

A mixture of4-(6-chloro-5-methoxy-pyrimidin-4-yloxy)-piperidine-1-carboxylic acidisopropyl ester (611 mg, 1.85 mmol),2-methyl-6-(methylsulfonyl)pyridin-3-amine (345 mg, 1.85 mmol),palladium acetate (37.2 mg, 0.166 mmol),2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phospha-bicyclo[3.3.3]undecane (118μl, 0.332 mmol), and sodium 2-methylpropan-2-olate (267 mg, 2.78 mmol)in 15 mL dioxane was heated under microwave irradiation at 120° C. After2 h, mixture was purified by HPLC; fractions containing product werecollected and concentrated. Residue was extracted with 1M NaOH andCH₂Cl₂. Organic phases were dried over MgSO₄, filtered, andconcentrated. Residue was re-purified by column chromatography(AcOEt/hexane 5:1). Fractions containing product were concentrated,treated with 4M HCl and concentrated to give4-[6-(6-methanesulfonyl-2-methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester as a white solid (HCl salt, 326 mg, 34%). ¹HNMR(MeOH-d₄, 400 MHz) δ 1.23-1.24 (d, J=6.2 Hz, 6H), 1.77-1.85 (m, 2H),2.01-2.07 (m, 2H), 2.59 (s, 3H), 3.20 (s, 3H), 3.40-3.46 (m, 2H),3.71-3.77 (m, 2H), 3.98 (s, 3H), 4.83-4.89 (m, 1H), 5.41-5.46 (m, 1H),7.97-7.99 (d, J=8.3 Hz, 1H), 8.11 (s, 1H), 8.29-8.31 (d, J=8.3 Hz, 1H).Exact mass calculated for C₂₁H₂₉N₅O₆S 479.18, found 480.2 (MH⁺).

Example 9.20 Preparation of4-[6-(6-methanesulfonyl-4-methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound 85) Step A: Preparation of6-methanesulfonyl-4-methyl-pyridin-3-ylamine

A mixture of 6-chloro-4-methyl-pyridin-3-ylamine (1.53 g, 11 mmol),sodium methanesulfinate (1.60 g, 16 mmol), copper catalyst (0.50 g, 0.99mmol), and N¹,N²-dimethylethane-1,2-diamine (0.214 mL, 2.0 mmol) in 20mL DMSO was heated under microwave irradiation at 150° C. After 2 h,mixture was poured into ca. 200 mL water and extracted five times withca. 200 mL AcOEt. Organic phases were dried over MgSO₄, filtered, andconcentrated. Residue was purified by column chromatography(AcOEt/hexane 5:1→AcOEt) to give6-methanesulfonyl-4-methyl-pyridin-3-ylamine as a white solid (0.534 g,27%). ¹HNMR (DMSO-d₆, 400 MHz) δ 2.4 (s, 3H), 3.08 (s, 3H), 6.08 (s,2H), 7.59 (s, 1H), 7.97 (s, 1H). Exact mass calculated for C₇H₁₀N₂O₂S186.05, found 187.0 (MH⁺).

Step B: Preparation of4-[6-(6-methanesulfonyl-4-methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound 85)

A mixture of4-(6-chloro-5-methoxy-pyrimidin-4-yloxy)-piperidine-1-carboxylic acidisopropyl ester (570 mg, 1.73 mmol),6-methanesulfonyl-4-methyl-pyridin-3-ylamine (272 mg, 1.46 mmol),palladium acetate (27.3 mg, 0.122 mmol),2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phospha-bicyclo[3.3.3]undecane (87μl, 0.245 mmol), and sodium 2-methylpropan-2-olate (249 mg, 2.59 mmol)in 4.5 mL dioxane was heated under microwave irradiation at 120° C.After 4 h, mixture was purified by HPLC; fractions containing pureproduct were collected and concentrated. Residue was treated with 4M HClin dioxane, concentrated, and dried under high vacuum to give4-[6-(6-methanesulfonyl-4-methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester as a white solid (HCl salt, 261 mg, 29%). ¹HNMR(MeOH-d₄, 400 MHz) δ 1.23-1.24 (d, J=6.2 Hz, 6H), 1.75-1.81 (m, 2H),1.97-2.04 (m, 2H), 2.40 (s, 3H), 3.17 (s, 3H), 3.39-3.46 (m, 2H),3.71-3.77 (m, 2H), 3.92 (s, 3H), 4.82-4.88 (m, 1H), 5.35-5.40 (m, 1H),7.99 (s, 1H), 7.99 (s, 1H), 8.96 (s, 1H). Exact mass calculated forC₂₁H₂₉N₅O₆S 479.18, found 480.4 (MH⁺).

Example 9.21 Preparation of4-[5-methoxy-6-(2-methyl-6-propylsulfanyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound 86) Step A: Preparation of2-methyl-6-propylsulfanyl-pyridin-3-ylamine

A mixture of 6-fluoro-2-methyl-pyridin-3-ylamine (2.01 g, 16 mmol),propane-1-thiol (3.0 mL, 33 mmol), and potassium hydroxide (1.8 g, 32mmol) in 3 mL EtOH were heated under microwave irradiation at 100° C.for 1 h and then at 150° C. for 2 h. Mixture was extracted with CH₂Cl₂and brine. Organic phases were dried over MgSO₄, filtered, andconcentrated. Residue was purified by column chromatography(hexane/AcOEt 2:1) to give 2-methyl-6-propylsulfanyl-pyridin-3-ylamine(2.18 g, 75% yield) as a colorless oil. ¹HNMR (CDCl₃, 400 MHz) δ0.99-1.03 (t, J=7.3 Hz, 3H), 1.64-1.73 (m, 2H), 2.39 (s, 3H), 3.02-3.05(t, J=7.3 Hz, 2H), 3.48 (s, 2H), 6.82-6.84 (d, J=8.2 Hz, 1H), 6.93-6.95(d, J=8.2 Hz, 1H). Exact mass calculated for C₉H₁₄N₂S 182.09, found183.0 (MH⁺).

Step B: Preparation of4-[5-methoxy-6-(2-methyl-6-propylsulfanyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound 86)

A mixture of4-(6-chloro-5-methoxy-pyrimidin-4-yloxy)-piperidine-1-carboxylic acidisopropyl ester (0.966 g, 2.93 mmol),2-methyl-6-propylsulfanyl-pyridin-3-ylamine (0.545 g, 2.99 mmol),palladium acetate (0.0375 g, 0.167 mmol),2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phospha-bicyclo[3.3.3]undecane(0.119 mL, 0.335 mmol), and sodium 2-methylpropan-2-olate (0.422 g, 4.39mmol) in 15 mL dioxane was heated under microwave irradiation at 120° C.After 2 h, mixture was purified by HPLC; fractions containing pureproduct were collected, partly concentrated, and residue was extractedwith CH₂Cl₂ and 1M NaOH. Organic phases were dried over MgSO₄, filtered,and concentrated to give4-[5-methoxy-6-(2-methyl-6-propylsulfanyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester as a thick oil (0.509 g, 36%). ¹HNMR (MeOH-d₄, 400MHz) δ 1.00-1.04 (t, J=7.3 Hz, 3H), 1.23-1.24 (d, J=6.2 Hz, 6H),1.66-1.78 (m, 4H), 1.96-2.02 (m, 2H), 2.37 (s, 3H), 3.06-3.10 (t, J=7.3Hz, 2H), 3.36-3.42 (m, 2H), 3.71-3.77 (m, 2H), 3.88 (s, 3H), 4.81-4.87(m, 1H), 5.28-5.34 (m, 1H), 7.09-7.11 (d, J=8.3 Hz, 1H), 7.57-7.59 (d,J=8.3 Hz, 1H), 7.84 (s, 1H). Exact mass calculated for C₂₃H₃₃N₅O₄S475.23, found 476.1 (MH⁺).

Example 9.22 Preparation of4-{5-methoxy-6-[2-methyl-6-(propane-1-sulfonyl)-pyridin-3-ylamino]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester (Compound 87)

A solution of4-[5-methoxy-6-(2-methyl-6-propylsulfanyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (498 mg, 1.05 mmol) in 25 mL CH₂Cl₂ was cooled inan ice-bath and MCPBA (max. 77% pure, 364 mg, 2.10 mmol) was added.After stirring under ice cooling for 1 h, more MCPBA (99 mg, 0.44 mmol)was added. After 3 h, solution was transferred into a sepratory funneland extracted with 1M NaOH and CH₂Cl₂. Organic phases were dried overMgSO₄, filtered, and concentrated. Residue was purified by columnchromatography (hexane/AcOEt 1:1); fractions containing product werecollected, 4M HCl in dioxane was added, and concentrated to give4-{5-methoxy-6-[2-methyl-6-(propane-1-sulfonyl)-pyridin-3-ylamino]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester a white solid (HCl salt, 489 mg, 86%). ¹HNMR(MeOH-d₄, 400 MHz) δ 0.98-1.00 (t, J=7.4 Hz, 3H), 1.23-1.25 (d, J=6.2Hz, 6H), 1.66-1.80 (m, 4H), 1.99-2.05 (m, 2H), 2.58 (s, 3H), 3.28-3.34(m, 2H), 3.40-3.45 (m, 2H), 3.69-3.75 (m, 2H), 3.95 (s, 3H), 4.82-4.86(m, 1H), 5.35-5.40 (m, 1H), 7.90-7.92 (d, J=8.4 Hz, 1H), 8.03 (s, 1H),8.48-8.50 (d, J=8.4 Hz, 1H). Exact mass calculated for C₂₃H₃₃N₅O₄S475.23, found 508.4 (MH⁺).

Example 9.23 Preparation of4-[6-(6-ethylsulfanyl-2-methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound 88) Step A: Preparation of6-ethylsulfanyl-2-methyl-pyridin-3-ylamine

6-Ethylsulfanyl-2-methyl-pyridin-3-ylamine was prepared in similarmanner as described in Example 9.21, Step A, to afford a yellow oil(0.99 g, 37%). ¹HNMR (MeOH-d₄, 400 MHz) a 1.30-1.34 (t, J=7.3 Hz, 3H),2.39 (s, 3H), 3.04-3.10 (q, J=7.3 Hz, 2H), 3.49 (s, 2H), 6.83-6.85 (d,J=8.2 Hz, 1H), 6.94-6.96 (d, J=8.2 Hz, 1H). Exact mass calculated forC₈H₁₂N₂S 168.07, found 169.2 (MH⁺).

Step B: Preparation of4-[6-(6-ethylsulfanyl-2-methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound 88)

4-[6-(6-Ethylsulfanyl-2-methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester was prepared in similar manner as described inExample 9.21, Step B, to afford a colorless oil (461 mg, 33%). ¹HNMR(CDCl₃, 400 MHz) δ 1.24-1.25 (d, J=6.3 Hz, 6H), 1.35-1.39 (t, J=7.4 Hz,3H), 1.78-1.85 (m, 2H), 2.00-2.05 (m, 2H), 2.50 (s, 3H), 3.11-3.17 (q,J=7.4 Hz, 2H), 3.37-3.44 (m, 2H), 3.75-3.81 (m, 2H), 3.95 (s, 3H),4.91-4.97 (m, 1H), 5.33-5.38 (m, 1H), 6.79 (s, 1H), 7.06-7.09 (d, J=8.5Hz, 1H), 8.08-8.11 (d, J=8.5 Hz, 1H), 8.10 (s, 11H). Exact masscalculated for C₂₂H₃₁N₅O₄S 461.21, found 462.5 (MH⁺).

Example 9.24 Preparation of4-[6-(6-ethanesulfonyl-2-methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound 89)

4-[6-(6-Ethanesulfonyl-2-methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester was prepared in a similar manner as described inExample 9.22 to afford a white solid (HCl salt, 459 mg, 89%). ¹HNMR(CDCl₃, 400 MHz) δ 1.26-1.32 (m, 9H), 1.80-1.87 (m, 2H), 2.02-2.07 (m,2H), 2.66 (s, 3H), 3.34-3.45 (m, 4H), 3.75-3.81 (m, 2H), 4.00 (s, 3H),4.91-4.97 (m, 1H), 5.37-5.43 (m, 1H), 7.35 (s, 1H), 7.96-7.98 (d, J=8.6Hz, 1H), 8.21 (s, 1H) 9.00-9.02 (d, J=8.6 Hz, 1H). Exact mass calculatedfor C₂₂H₃₁N₅O₆S 493.2, found 494.5 (MH⁺).

Example 9.25 Preparation of4-[6-(6-isopropylsulfanyl-2-methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound 90) Step A: Preparation of6-isopropylsulfanyl-2-methyl-pyridin-3-ylamine

6-Isopropylsulfanyl-2-methyl-pyridin-3-ylamine was prepared in similarmanner as described in Example 9.21, Step A, to afford a yellow oil(1.76 g, 38%). ¹HNMR (CDCl₃, 400 MHz) δ 1.31-1.33 (d, J=6.7 Hz, 6H),2.40 (s, 3H), 3.52 (s, 2H), 3.66-3.73 (m, 1H), 6.81-6.83 (d, J=8.1 Hz,1H), 6.99-7.01 (d, J=8.1 Hz, 1H). Exact mass calculated for C₉H₁₄N₂S182.09, found 183.1 (MH⁺).

Step B: Preparation of4-[6-(6-isopropylsulfanyl-2-methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester

4-[6-(6-isopropylsulfanyl-2-methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester was prepared in similar manner as described inExample 9.21, Step B, to afford a colorless oil (445 mg, 29%). ¹HNMR(CDCl₃, 400 MHz) δ 1.25-1.27 (d, J=6.2 Hz, 6H), 1.37-1.39 (d, J=6.8 Hz,6H), 1.79-1.85 (m, 2H), 1.99-2.05 (m, 2H), 2.50 (s, 3H), 3.37-3.44 (m,2H), 3.75-3.92 (m, 3H), 3.95 (s, 3H), 4.91-4.97 (m, 1H), 5.34-5.38 (m,1H), 6.81 (s, 1H), 7.09 (d, J=8.5 Hz, 1H), 8.09 (s, 1H), 8.13-8.15 (d,J=8.5 Hz, 1H). Exact mass calculated for C₂₃H₃₃N₅O₄S 475.23, found 476.2(MH⁺).

Example 9.26 Preparation of4-{5-methoxy-6-[2-methyl-6-(propane-2-sulfonyl)-pyridin-3-ylamino]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester (Compound 91)

4-{5-Methoxy-6-[2-methyl-6-(propane-2-sulfonyl)-pyridin-3-ylamino]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester was prepared in a similar manner as described inExample 9.22 to afford a white solid (HCl salt, 410 mg, 82%). ¹HNMR(MeOH-d₄, 400 MHz) δ 1.25-1.26 (d, J=6.2 Hz, 6H), 1.28-1.30 (d, J=6.8Hz, 6H), 1.76-1.82 (m, 2H), 2.01-2.07 (m, 2H), 2.61 (s, 3H), 3.29-3.36(m, 2H), 3.65-3.81 (m, 3H), 3.97 (s, 3H), 4.83-4.89 (m, 1H), 4.90-4.95(m, 1H), 7.92-7.94 (d, J=8.4 Hz, 1H), 8.07 (s, 1H), 8.51-8.53 (d, J=8.4Hz, 1H). Exact mass calculated for C₂₃H₃₃BrN₅O₆S 507.22, found 508.5(MH⁺).

Example 9.27 Preparation of4-{6-[6-(2-hydroxy-ethylsulfanyl)-2-methyl-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester (Compound 79). Step A: Preparation of2-(6-methyl-5-nitro-pyridin-2-ylsulfanyl)-ethanol

To an ice-cooled solution of 6-chloro-2-methyl-3-nitropyridine (2.17 g,13 mmol) in 2-mercaptoethanol (5 mL, 71 mmol), potassium hydroxide (1.52g, 27 mmol) was added. Mixture was stirred at room temperature for 2 hand then extracted with NaOH solution and CH₂Cl₂. Organic phases weredried over MgSO₄, filtered, and concentrated to give2-(6-methyl-5-nitro-pyridin-2-ylsulfanyl)-ethanol as a brown oil (60%pure, 3.25 g, 72%). ¹HNMR (CDCl₃, 400 MHz) δ 2.87-2.90 (m, 6H),3.43-3.46 (t, J=5.6 Hz, 2H), 7.22-7.24 (d, J=8.7 Hz, 1H), 8.15-8.17 (d,J=8.7 Hz, 1H). Exact mass calculated for C₈H₁₀N₂O₃S 214.04, found 215.1(MH⁺).

Step B: Preparation of6-[2-(tert-butyl-dimethyl-silanyloxy)-ethylsulfanyl]-2-methyl-3-nitro-pyridine

A mixture of 2-(6-methyl-5-nitro-pyridin-2-ylsulfanyl)-ethanol (60%pure, 3.25 g, 9.1 mmol), 1H-imidazole (1.24 g, 18.2 mmol), andtert-butylchlorodimethylsilane (2.75 g, 18.2 mmol) in 20 mL DMF wasstirred at room temperature for 4 h. Solution was concentrated andresidue was extracted with water and CH₂Cl₂. Organic phases were driedover MgSO₄, filtered, and concentrated. Residue was purified by columnchromatography (hexane/AcOEt 30:1) to give6-[2-(tert-butyl-dimethyl-silanyloxy)-ethylsulfanyl]-2-methyl-3-nitro-pyridineas a yellow oil (2.39 g, 48%). ¹HNMR (CDCl₃, 400 MHz) δ .0.8 (s, 6H),0.90 (s, 9H), 2.85 (s, 3H), 3.39-3.42 (t, J=6.7 Hz, 2H), 3.85-3.89 (t,J=6.7 Hz, 2H), 7.13-7.15 (d, J=8.7 Hz, 1H), 8.10-8.13 (d, 1H). Exactmass calculated for C₁₄H₂₄N₂O₃SSi 328.13, found 329.1 (MH⁺).

Step C: Preparation of6-[2-(tert-butyl-dimethyl-silanyloxy)-ethylsulfanyl]-2-methyl-pyridin-3-ylamine

To a solution of6-[2-(tert-butyl-dimethyl-silanyloxy)-ethylsulfanyl]-2-methyl-3-nitro-pyridine(80, 2.67 g, 8.1 mmol) in 15 mL THF, zinc dust (1.6 g, 24 mmol) followedby 8.2 mL (8.2 mmol) 1M NH₄Cl solution was added. After stirring at roomtemperature for 3 h, more zinc dust (0.77 g, 8.13 mmol) and NH₄Cl (0.43g, 8.31 mmol) was added. After stirring for 4 h at mixture was filteredthrough celite and filtrate was extracted with CH₂Cl₂ and 1M NaOH.Organic phases were dried over MgSO₄, filtered, and concentrated.Residue was purified by column chromatography (Hexane/AcOEt 3:1→2:1) togive6-[2-(tert-butyl-dimethyl-silanyloxy)-ethylsulfanyl]-2-methyl-pyridin-3-ylamineas a yellowish oil (1.3 g, 54%). Exact mass calculated for C₂₅H₃₄BrN₅O₅563.17, found 564.3 (MH⁺).

Step C: Preparation of4-{6-[6-(2-hydroxy-ethylsulfanyl)-2-methyl-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester (Compound 79)

A mixture of4-(6-chloro-5-methoxy-pyrimidin-4-yloxy)-piperidine-1-carboxylic acidisopropyl ester (1.00 g, 3.03 mmol),6-[2-(tert-butyl-dimethyl-silanyloxy)-ethylsulfanyl]-2-methyl-pyridin-3-ylamine(0.85 g, 2.85 μmol), palladium acetate (0.0379 g, 0.169 mmol),2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phospha-bicyclo[3.3.3]undecane(0.120 mL, 0.338 mmol), and sodium 2-methylpropan-2-olate (0.437 g, 4.55mmol) in 20 nL dioxane were heated at 80° C. for 14 h. Mixture wastransferred into a separatory funnel and extracted with CH₂Cl₂ andbrine. Organic phases were dried over MgSO₄, filtered, and concentrated.To the residue, 4M HCl in dioxane (ca. 10 mL) was added and stirred atroom temperature for 1 h. Mixture was purified by HPLC; fractionscontaining pure product were collected, ammonium hydroxide was added (ca5 mL), and partly concentrated. Residue was extracted with 1M NaOH andCH₂Cl₂. Organic phases were dried over MgSO₄, filtered, and concentratedto give4-{6-[6-(2-hydroxy-ethylsulfanyl)-2-methyl-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester as a yellowish solid (HCl salt, 219 mg, 15%). ¹HNMR(CDCl₃, 400 MHz) δ 1.25-1.27 (d, J=6.3 Hz, 6H), 1.76-1.83 (m, 2H),1.99-2.05 (m, 2H), 2.50 (s, 3H), 3.27-3.29 (m, 2H), 3.37-3.44 (m, 2H),3.76-3.82 (m, 2H), 3.95 (s, 3H), 3.95-4.01 (m, 2H), 4.91-4.97 (m, 1H),5.33-5.38 (m, 1H), 5.66-5.68 (m, 1H), 6.82 (s, 1H), 5.33-5.38 (m, 1H),5.66-5.68 (m, 1H), 6.82 (s, 1H), 7.21-7.23 (d, J=8.5 Hz, 1H), 8.08 (s,1H), 8.17-8.19 (d, J=8.5 Hz, 1H). Exact mass calculated for C₂₂H₃₁N₅O₅S477.2, found 478.4 (MH⁺).

Example 9.28 Preparation of4-{6-[6-(2-hydroxy-ethanesulfonyl)-2-methyl-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester (Compound 92)

4-{6-[6-(2-Hydroxy-ethanesulfonyl)-2-methyl-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester was prepared in a similar manner as described inExample 9.22 to afford a white solid (HCl salt, 250 mg, 92%). ¹HNMR(MeOH-d₄, 400 MHz) δ 1.24-1.26 (d, J=6.2 Hz, 6H), 1.78-1.84 (m, 2H),2.01-2.07 (m, 2H), 2.60 (s, 3H), 3.41-3.46 (m, 2H), 3.42-3.46 (t, J=8.8Hz, 2H), 3.58-3.64 (m, 2H), 2.74-3.77 (t, J=8.8 Hz, 2H), 3.97 (s, 3H),4.82-4.87 (m, 1H), 5.40-5.45 (m, 1H), 5.48 (s, 1H), 7.94-7.96 (d, J=8.4,1H), 8.09 (s, 1H), 8.42-8.44 (d, J=8.4 Hz, 1H). Exact mass calculatedfor C₂₂H₃₁N₅O₇S 509.19, found 510.4 (MH⁺).

Example 9.29 Preparation of4-[5-hydroxy-6-(6-methanesulfonyl-2-methyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound 93)

To an ice-cooled solution of4-[6-(6-methanesulfonyl-2-methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (59 mg, 123 μmol) in 2 mL CH₂Cl₂, BBr₃ (1M inCH₂Cl₂ 0.123 mL, 0.123 mmol) was added. After stirring for 1 h underice-cooling, more BBr₃ (0.246 mL, 0.246 mmol) was added. After 1 h,mixture was quenched with NH₄OH solution, concentrated, and purified byHPLC to give4-[5-hydroxy-6-(6-methanesulfonyl-2-methyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester as a white solid (TFA salt, 17 mg, 24%). ¹HNMR(MeOH-d₄, 400 MHz) δ 1.22-1.23 (d, J=6.3 Hz, 6H), 1.70-1.78 (m, 2H),1.97-2.02 (m, 2H), 2.59 (s, 3H), 3.15 (s, 3H), 3.26-3.32 (m, 2H),3.82-3.88 (m, 2H), 4.81-4.87 (m, 1H), 5.27-5.32 (m, 1H), 7.88-7.90 (d,J=8.5 Hz, 1H), 7.95 (s, 1H), 8.67-8.69 (d, J=8.5 Hz, 1H). Exact masscalculated for C₂₀H₂₇N₅O₆S 465.17, found 466.2 (MH⁺).

Example 9.30 Preparation of4-[5-ethoxy-6-(6-methanesulfonyl-2-methyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound 94)

A mixture of4-[5-hydroxy-6-(6-methanesulfonyl-2-methyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (40.4 mg, 87 μmol) potassium carbonate (24 mg, 174μmol), and iodoethane (7.7 μl, 95 μmol) in 1 mL CH₃CN was stirred at 60°C. After 20 h, mixture was purified by HPLC; fractions containingproduct were partly concentrated and residue was extracted with CH₂Cl₂and 1M NaOH. Organic phases were dried over MgSO₄, filtered, 4M HCl indioxane (ca 0.5 mL) was added, and concentrated to give4-[5-ethoxy-6-(6-methanesulfonyl-2-methyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester as a white solid (HCl salt, 24.3 mg, 53%). ¹HNMR(MeOH-d₄, 400 MHz) δ 1.25-1.27 (d, J=6.2 Hz, 6H), 1.41-1.44 (t, J=5.5Hz, 3H), 1.74-1.80 (m, 2H), 2.01-2.06 (m, 2H), 2.62 (s, 3H), 3.21 (s,3H), 3.30-3.35 (m, 2H), 3.72-3.77 (m, 2H), 4.22-4.28 (q, J=5.5 Hz, 2H),4.83-4.88 (m, 1H), 5.38-5.43 (m, 1H), 7.93-7.96 (d, J=8.4 Hz, 1H), 8.09(s, 1H), 8.57-8.59 (d, J=8.4 Hz, 1H). Exact mass calculated forC₂₂H₃₁N₅O₆S 493.2, found 494.5 (MH⁺).

Example 9.31 Preparation of4-[5-isopropoxy-6-(6-methanesulfonyl-2-methyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound 95)

To a mixture of4-[5-hydroxy-6-(6-methanesulfonyl-2-methyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (41.1 mg, 88 μmol), triphenylphosphine (34.7 mg,132 μmol), propan-2-ol (6.4 mg, 106 μmol) in 1 mL THF, DIAD (21 μl,106μmol) was added. After stirring for 2 h at room temperature, the sameamount of reagent was added again. After stirring for 16 h, mixture waspurified by HPLC; fractions containing product were collected, partlyconcentrated, and extracted with 1M NaOH and CH₂Cl₂. Organic phases weredried, filtered, 4M HCl in dioxane (ca 0.5 mL) was added, andconcentrated to give4-[5-isopropoxy-6-(6-methanesulfonyl-2-methyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester as a white solid (HCl salt, 9.7 mg, 20%). ¹HNMR(MeOH-d₄, 400 MHz) δ 1.25-1.27 (d, J=6.3 Hz, 6H), 1.37-1.39 (d, J=6.1Hz, 6H), 1.75-1.81 (m, 2H), 2.01-2.07 (m, 2H), 2.62 (s, 3H), 3.20 (s,3H), 3.42-3.47 (m, 2H), 3.70-3.76 (m, 2H), 4.68-4.74 (m, 1H), 4.83-4.89(m, 1H), 5.37-5.42 (m, 1H), 7.91-7.94 (d, J=8.4 Hz, 1H), 8.09 (s, 1H),8.70-8.71 (d, J=8.4 Hz, 1H). Exact mass calculated for C₂₃H₃₃N₅O₆S507.22, found 508.5 (MH⁺).

Example 9.32 Preparation of4-[6-(6-methanesulfonyl-2-methyl-pyridin-3-ylamino)-5-propoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound 96)

4-[6-(6-Methanesulfonyl-2-methyl-pyridin-3-ylamino)-5-propoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester was obtained in a similar manner as described inExample 30 to afford a white solid (HCl salt, 38.2 mg, 81%). ¹HNMR(MeOH-d₄, 400 MHz) δ 1.02-1.06 (t, J=7.4 Hz, 3H), 1.22-1.24 (d, J=6.2Hz, 6H), 1.75-1.84 (m, 4H), 2.00-2.05 (m, 2H), 2.59 (s, 3H), 3.19 (s,3H), 3.40-3.45 (m, 2H), 3.71-3.76 (m, 2H), 4.10-4.13 (t, J=6.6 Hz, 2H),4.82-4.88 (m, 1H), 4.36-4.41 (m, 1H), 7.92-7.95 (d, J=8.5 Hz, 1H), 8.09(s, 1H), 8.51-8.53 (d, J=8.5 Hz, 1H). Exact mass calculated forC₂₃H₃₃N₅O₆S 507.22, found 508.4 (MH⁺).

Example 9.33 Preparation of4-[6-(6-Methanesulfonyl-2-methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid 1-ethyl-propyl ester (Compound 97) Step A: Preparation of4-(6-Chloro-5-methoxy-pyrimidin-4-yloxy)-piperidine-1-carboxylic acidtert-butyl ester

A solution of 4,6-dichloro-5-methoxy-pyrimidine (5.62 g, 27.9 mmol) and4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (5.02 g, 27.9mmol) in 200 mL THF was chilled to 0° C. A 1.0 M solution of potassiumt-butoxide (30.7 mL, 30.7 mmol) was added drop-wise with stirring andthe resulting mixture then was allowed to stir at 0° C. for one hour.Saturated ammonium chloride (100 mL) was added and the solutionextracted with ethyl acetate. The organic phase was washed with brineand dried with magnesium sulfate, solvent removed to yield 9.10 g (94.8%yield). ¹HNMR (CDCl₃, 400 MHz) δ 1.48 (s, 2H), 1.79-1.83 (m, 2H),1.99-2.04 (m, 2H), 3.33-3.39 (m, 2H), 3.72-3.77 (m, 2H), 3.91 (s, 3H),5.30-5.38 (m, 1H), 8.26 (s, 1H). Exact mass calculated for C₁₅H₂₂ClN₃O₄:343.13, found: 344.3 (MH⁺).

Step B: Preparation of4-Chloro-5-methoxy-6-(piperidin-4-yloxy)-pyrimidine

4-(6-Chloro-5-methoxy-pyrimidin-4-yloxy)-piperidine-1-carboxylic acidtert-butyl ester (5.0 g, 14.5 mmol) was taken up in 200 mL of 4N HCl indioxane and 200 mL MeOH, stirred at 60° C. for 3 h. Solvent was removedto yield hydrochloride (3.9 g, 95.7% yield) a pale yellow solid, and thematerial used directly with out further purification. ¹HNMR (CDCl₃, 400MHz) δ 2.02-2.05 (m, 2H), 2.17-2.20 (m, 2H), 3.13-3.19 (m, 4H), 3.88 (s,3H), 5.37-5.40 (m, 1H), 8.39 (s, 1H), 9.30 (bs, 2H). Exact masscalculated for C₁₀H₁₄ClN₃O₂: 243.08, found: 244.2 (MH⁺).

Step C: Preparation of4-(6-Chloro-5-methoxy-pyrimidin-4-yloxy)-piperidine-1-carboxylic acid1-ethyl-propyl ester

Pentan-3-ol (0.88 g, 9.99 mmol) and di-imidazol-1-yl-methanone (1.39,8.57 mmol) were added to THF (10 mL) and stirred at 50° C. for one hour.DIPEA (1.38 g, 10.7 mmol) and4-chloro-5-methoxy-6-(piperidin-4-yloxy)-pyrimidine HCl (2.00 g, 7.14mmol) were added, the vessel sealed and heated by microwave at 150° C.for one hour. Upon cooling the reaction mixture was partitioned betweenwater and Ethyl Acetate, the organic phase washed with brine and driedwith Sodium Sulfate. The crude material was purified by columnchromatograph (silica gel) with 10-30% EtOAc/Hexanes to yield 1.0 grams(39%) of the desired product, as a white solid. ¹HNMR (CDCl₃, 400 MHz) δ0.91(t, J=7.83 Hz, 6H), 1.55-1.63 (m, 4H), 1.78-1.88 (m, 2H), 1.99-2.08(m, 2H), 3.39-3.46 (m, 2H), 3.78-3.85 (m, 2H), 3.92 (s, 3H), 4.67 (m,1H), 5.36-5.43 (m, 1H), 8.26 (s, 1H). Exact mass calculated forC₁₆H₂₄ClN₃O₄: 357.15, found: 358.3 (MH⁺).

Step D: Preparation of4-[6-(6-Methanesulfonyl-2-methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid 1-ethyl-propyl ester

4-(6-Chloro-5-methoxy-pyrimidin-4-yloxy)-piperidine-1-carboxylic acid1-ethyl-propyl ester, (0.50 g, 1.40 mmol) and6-methanesulfonyl-2-methyl-pyridin-3-ylamine (0.26 g, 1.40 mmol) andpalladium acetate (0.062 g, 0.28 mmol) and2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phospha-bicyclo[3.3.3]undecane(0.191 g, 0.559 mmol) were combined in 50 mL dioxane, purged withnitrogen and a 1M solution of potassium t-butoxide in THF (2.79 mL, 2.79mmol) added dropwise. The reaction was heated to 100° C. and stirred for2 hours, then was filtered, concentrated, acidified and purified by prepHPLC, the desired fractions partitioned between saturated sodiumhydrogen carbonate and ethyl acetate, the organic phase washed withbrine and dried with magnesium sulfate to yield (15 mg, 0.029 mmol,2.11% yield) desired product, as a white solid. ¹HNMR (CDCl₃, 400 MHz) δ0.91(t, J=7.33 Hz, 6H), 1.54-1.64 (m, 4H), 1.77-1.87 (m, 2H), 1.99-2.08(m, 2H), 2.65 (s, 3H), 3.19 (s, 3H), 3.39-3.46 (m, 2H), 3.78-3.85 (m,2H), 4.00 (s, 3H), 4.67 (pent, J=6.32 Hz, 1H), 5.36-5.43 (hept, J=3.79Hz, 1H), 7.31 (bs, 1H), 7.96 (d, J=8.34 Hz, 1H), 8.20 (s, 1H), 9.02 (d,J=8.59 Hz, 1H). Exact mass calculated for C₂₃H₃₃N₅O₆S: 507.22, found:508.5 (MH⁺).

Example 9.34 Preparation of(R)-4-[6-(6-Methanesulfonyl-2-methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid sec-butyl ester (Compound 98 as the R-enantiomer)

The title compound was prepared in a similar manner as described inExample 9.33 (55 mg, 0.11 mmol, 19.2% yield). ¹HNMR(CDCl₃, 400 MHz) δ0.93 (t, J=7.07 Hz, 3H), (d, J=6.32 Hz, 3H), 1.52-1.63 (m, 2H),1.77-1.87 (m, 2H), 1.99-2.08 (m, 2H), 2.65 (s, 3H), 3.19 (s, 3H),3.39-3.46 (m, 2H), 3.76-3.85 (m, 2H), 4.01 (s, 3H), 4.73-4.81 (m, 1H),5.37-5.43 (m, 1H), 7.33 (bs, 1H), 7.95 (d, J=8.59 Hz, 1H), 8.20 (s, 1H),9.00 (d, J=8.59 Hz, 1H). Exact mass calculated for C₂₂H₃₁N₅O₆S: 493.20,found: 494.4 (MH⁺).

Example 9.35 Preparation of(S)-4-[6-(6-Methanesulfonyl-2-methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid sec-butyl ester. (Compound 98 as the S-enantiomer)

The title compound was prepared in a similar manner as described inExample 9.33 (15 mg, 0.029 mmol, 2.11% yield). ¹HNMR (CDCl₃, 400 MHz) δ0.87-0.95 (m, 3H), 1.18-1.28 (m, 3H), 1.52-1.67 (m, 2H), 1.77-1.87 (m,2H), 1.99-2.08 (m, 2H), 2.65 (s, 3H), 3.19 (s, 3H), 3.42 (m, 2H), 3.82(m, 2H), 4.00 (s, 3H), 4.67-4.78 (m, 1H), 5.36-5.43 (m, 1H), 7.31 (bs,1H), 7.96 (d, J=8.54 Hz, 1H), 8.20 (s, 1H), 9.02 (d, J=9.60 Hz, 1H).Exact mass calculated for C₂₂H₃₁N₅O₆S: 493.20, found: 494.4 (MH⁺).

Example 9.36 Preparation of4-[6-(6-Methanesulfonyl-2-methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid cyclopentyl ester (Compound 99)

The title compound was prepared in a similar manner as described inExample 9.33 (60 mg, 0.12 mmol, 21.1% yield). ¹HNMR (CDCl₃, 400 MHz) δ1.55-1.65 (m, 2H), 1.67-1.76 (m, 4H), 1.79-1.91 (m, 4H), 1.99-2.09 (m,2H), 2.65 (s, 3H), 3.19 (s, 3H), 3.39-3.46 (m, 2H), 3.76-3.85 (m, 2H),4.01 (s, 3H), 5.11-5.13 (m, 1H), 5.40 (m, 1H), 7.33 (bs, 1H), 7.95 (d,J=8.34 Hz, 1H), 8.20 (s, 1H), 9.00 (d, J=8.59 Hz, 1H). Exact masscalculated for C₂₃H₃₁N₅O₆S: 505.20, found: 506.4 (MH⁺).

Example 9.37 Preparation of4-[6-(6-Hydroxymethyl-4-methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound 100) Step A: Preparation of(4-methyl-5-nitropyridin-2-yl)methanol.

To a solution of the mixture of 2,4-dimethyl-5-nitropyridine (3.0 g, 20mmol) in 30 ml of dioxane, was selenium oxide (2.8 g, 25 mmol) added atan ambient temperature. The reaction was refluxed for 10 hrs. Thereaction was cooled to room temperature and concentrated under vacuum.The residue was poured into water and extracted with ethyl acetate. Theorganic layer was dried over MgSO₄ and concentrated under vacuum. Thecrude mixture of the aldehyde was diluted in methanol (30 mL) and sodiumborohydride (0.74 g, 20 mmol) was added portionwise at 0° C. Afterstirred for 1 hr, the reaction was quenched with water (20 mL) andconcentrated under vacuum. The reaction was extracted with ethyl acetateand dried over MgSO₄. The ethyl acetate was dried under vacuum andpurified under SiO₂ with 50% ethyl acetate in hexane to afford(4-methyl-5-nitropyridin-2-yl)methanol in 83% (2.7 g). ¹HNMR (CDCl₃, 400MHz) δ 2.65 (s, 1H), 4.60 (d, J=8.1, 2H), 5.81 (t, J=8.1, 1H), 7.67 (s,1H), 9.21 (s, 1H).

Step B: Preparation of2-((tert-butyldiphenylsilyloxy)methyl)-4-methyl-5-nitropyridine

To a solution of (4-methyl-5-nitropyridin-2-yl)methanol (1.2 g, 7.1mmol) in 5 mL of CH₂Cl₂, were added tert-butylchlorodiphenylsilane (2.0g, 7.1 mmol) and imidazole (0.049 g, 0.71 mmol) at an ambienttemperature. The reaction was stirred at 25° C. for 2 hrs. The reactionwas poured into H₂O, extracted with ethyl acetate, and dried over MgSO₄.The ethyl acetate was concentrated under vacuum and purified over SiO₂to afford the desired compound2-((tert-butyldiphenylsilyloxy)methyl)-4-methyl-5-nitropyridine in 90%(2.6 g). ¹HNMR (CDCl₃, 400 MHz) δ 1.12 (s, 9H), 2.78 (s, 3H), 4.85 (s,2H), 7.21 (s, 1H), 7.24˜7.89 (m, 1H), 9.15 (s, 1H).

Step C: Preparation of6-((tert-butyldiphenylsilyloxy)methyl)-4-methylpyridin-3-amine

To a solution of2-((tert-butyldiphenylsilyloxy)methyl)-4-methyl-5-nitropyridine (1.5 g,3.7 mmol) in 20 ml of sat. NH₄Cl, were added zinc (1.7 g, 26 mmol)portionwise at 0° C. for 10 min. The reaction was stirred at the sametemperature for 1 hr. The reaction was added with ethyl acetate (20 mL)and stirred for additional 1 hr. The organic layer was taken up, washedwith H₂O, and dried over MgSO₄. The ethyl acetate was concentrated undervacuum to afford6-((tert-butyldiphenylsilyloxy)methyl)-4-methylpyridin-3-amine in 72%(1.0 g). The compound was used for the next step without furtherpurification. ¹HNMR (CDCl₃, 400 MHz) δ 1.10 (s, 9H), 2.21 (s, 3H), 4.64(s, 2H), 5.01˜5.13 (b, 2H), 7.12 (s, 1H), 7.31-7.71 (m, 1H), 7.89 (s,1H). Exact mass calculated for C₂₃H₂₈N₂OSi 376.57, found 377.4 (MH⁺).

Step D: Preparation of4-[6-(6-Hydroxymethyl-4-methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound 100)

To a solution of isopropyl4-(6-chloro-5-methoxypyrimidin-4-yloxy)piperidine-1-carboxylate (1.5 g,4.548 mmol) in 100 mL of THF, were added6-((tert-butyldiphenylsilyloxy)methyl)-4-methylpyridin-3-amine (1.713 g,4.5 mmol),2,8,9-trilsobutyl-2,5,8,9-tetraaza-1-phospha-bicyclo[3.3.3]undecane(0.1558 g, 0.4548 mmol), Pd(OAc)₂ (0.05106 g, 0.2274 mmol), and Na-t-OBu(1.049 g, 10.92 mmol) at an ambient temperature. The reaction wasstirred at 75° C. for 2 hrs. The reaction was cooled to room temperatureand poured into H₂O. The organics were extracted with ethyl acetate anddried over MgSO₄. The ethyl acetate was concentrated under vacuum anddissolved in THF (10 mL). The solution was treated with 1.0 M TBAF atroom temperature. After stirring for 2 hrs, the reaction wasconcentrated under vacuum and poured into H₂O. The organic compound wasextracted with ethyl acetate and dried over MgSO₄. The organic layer wasconcentrated under vacuum and purified over SiO₂ to afford isopropyl4-(6-(6-(hydroxymethyl)-3-methylpyridin-2-ylamino)-4-methoxypyrimidin-4-yloxy)piperidine-1-carboxylatein 33.1% (650 mg). ¹HNMR (CDCl₃, 400 MHz) δ 1.21 (d, 6H), 1.62-1.69 (m,2H), 1.84-1.86 (m, 2H), 2.41 (s, 3H), 2.52 (s, 3H), 3.21-3.65 (m, 2H),3.64-3.72 (m, 2H), 3.82 (s, 2H), 4.80-4.91 (m, 1H), 5.31˜5.43 (m, 1H),7.80 (s, 1H), 8.01 (s, 1H), 8.89 (s, 1H) Exact mass calculated forC₂₁H₂₉N₅O₆ 431.49, found 432.4 (MH⁺).

Example 9.37 Preparation of4-[6-(6-Cyano-4-methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound 99) Step A: Preparation of4-methyl-5-nitropicolinonitrile

To a solution of 2-bromo-4-methyl-5-nitropyridine (5.0 g, 23 mmol) in 20ml of THF, were added Zn(CN)₂ (6.8 g, 58 mmol), and Pd(PPh₃)₄ (2.7 g,2.3 mmol) at an ambient temperature. The reaction was stirred at 130° C.for 2 hrs. The reaction was cooled to room temperature and poured intoH₂O. The reaction was extracted with ethyl acetate and dried over MgSO₄.The organic layer was concentrated under vacuum to afford4-methyl-5-nitropicolinonitrile 82% (3.1 g) which was used for the nextstep without further purification. ¹HNMR (CDCl₃, 400 MHz) δ 8.90 (s,1H), 7.12 (s, 1H), 2.54 (s, 3H).

Step B: Preparation of 5-amino-4-methylpicolinonitrile

4-methyl-5-nitropicolinonitrile (7.0 g, 43 mmol) was suspended in aq.NH₄Cl (200 mL) and cooled to 0° C. Zinc was added portionwise for 30 minand stirred for 1 hr. The reaction was added with ethyl acetate (200 mL)and stirred for 2 hrs. The reaction was filtered and the organic layerwas taken up, dried over MgSO₄, and concentrated over vacuum. The solidwas triturated with 50% ethyl acetate in hexane to give5-amino-4-methylpicolinonitrile in 67% (4.56 g). ¹HNMR (CDCl₃, 400 MHz)δ 7.98 (s, 1H), 7.21 (s, 1H), 5.42˜5.48 (b, 2H), 2.54 (s, 3H). Exactmass calculated for C₇H₇N₃ 133.15, found 134.21 (MH⁺).

Step C: Preparation of4-[6-(6-Cyano-4-methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound 99)

To a solution of isopropyl4-(6-chloro-5-methoxypyrimidin-4-yloxy)piperidine-1-carboxylate (0.3 g,0.91 mmol) in dioxane (3 mL), were added 5-amino-4-methylpicolinonitrile(0.12 g, 0.91 mmol),2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phospha-bicyclo[3.3.3]undecane(0.031 g, 0.091 mmol), Pd(OAc)₂ (0.10 g, 0.45 mmol), and NaO-t-Bu (0.21g, 2.2 mmol) at an ambient temperature. The reaction was warmed to 75°C. and stirred for 2 hrs. After cooling to room temperature, thereaction was poured into H₂O and extracted with ethyl acetate. Theorganic layer was dried over MgSO₄ and concentrated under vacuum. Theresidue was purified over SiO₂ to afford isopropyl4-(6-(6-cyano-4-methylpyridin-3-ylamino)-5-methoxypyrimidin-4-yloxy)piperidine-1-carboxylatein 31% (102 mg). ¹HNMR (CDCl₃, 400 MHz) δ 1.21 (d, J=4.71, 6H),1.71-1.75 (m, 2H), 1.95-2.01 (m, 2H), 2.31 (s, 3H), 2.62 (s, 3H),3.32-3.41 (m, 2H), 3.64-3.71 (m, 2H), 4.85-4.90 (m, 1H), 5.35˜5.41 (m,1H), 7.81 (s, 1H), 8.10 (s, 1H), 8.82 (d, J=4.71 Hz, 1H). Exact masscalculated for C₂₁H₂₆N₆O₄ 426.47, found 427.51 (MH⁺).

Example 9.38 Preparation of{6-[1-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-5-methoxy-pyrimidin-4-yl}-(6-methanesulfonyl-2-methyl-pyridin-3-yl)-amine(Compound 101)

A mixture of4-chloro-6-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-5-methoxy-pyrimidine(1.78 g, 5.03 mmol), 6-Methanesulfonyl-2-methyl-pyridin-3-ylamine (1.12g, 6.04 mmol), palladium acetate (102 mg, 0.45 mmol),2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phospha-bicyclo[3.3.3]undecane (322μl, 0.91 mmol) and sodium tert-butoxide (725 mg, 7.54 mmol) in 30 mL ofdioxane was heated under microwave irradiation at 150° C. for 1 hr.Additional 40 mL of dioxane were added and the mixture was refluxedunder 130° C. After 65 hr, mixture was purified by HPLC. Fractions withproduct were collected, concentrated, and recrystalized with hotethanol. 4N HCl in dioxane (ca 1 mL) and acetonitrile (ca 3 mL) wereadded and concentrated to give{6-[1-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-5-methoxy-pyrimidin-4-yl}-(6-methanesulfonyl-2-methyl-pyridin-3-yl)-amineas white solid (HCl salt, 360 mg, 13.3%). ¹HNMR (DMSO-d₆, 400 MHz) δ1.19-1.21 (d, J=6.82 Hz, 6H), 1.83-1.85 (m, 2H), 2.06-2.08 (m, 2H), 2.51(s, 3H), 2.81-2.84 (sept, J=6.82 Hz, 1H), 3.57-3.59 (m, 2H), 3.75-3.77(m, 2H), 3.87 (s, 1H), 5.31-3.39 (m, 1H), 7.89-7.91 (d, J=8.34 Hz, 1H),8.07 (s, 1H), 8.23-8.25 (d, J=8.34 Hz, 1H) 8.69 (s, 1H). Exact masscalculated for C₂₂H₂₉N₇O₅S 503.2, found 504.2 (MH⁺).

Example 9.39 Preparation of isopropyl4-(6-(2,4-dimethyl-6-(methylsulfonyl)pyridin-3-ylamino)-5-methoxypyrimidin-4-yloxy)piperidine-1-carboxylate(Compound 102) Step A: Preparation of 2,4-dimethylpyridin-3-amine

2,4-dimethylnicotinic acid (3.0 g, 20 mmol) was added in SOCl2 (20 mL)at 0° C. and warmed to 60° C. After stirring for 1 hr, the reaction wasconcentrated under vacuum. The residue was dissolved in acetone (20 mL)and NaN₃ (1.9 g, 30 mmol) followed by H₂O (20 mL). The reaction waswarmed to 70° C. and stirred for 1 hr at the same temperature. Thereaction was cooled to room temperature and concentrated under vacuum toa half volume and poured into H₂O (50 mL) and extracted with ethylacetate (50 mL×5) and dried over MgSO₄. The ethyl acetate wasconcentrated under vacuum to afford the crude compound. The compound wasused for the next step without further purification. ¹HNMR (CDCl₃, 400MHz) δ 2.10 (s, 3H), 2.30 (s, 3H), 4.65-4.70 (b, 2H), 6.85 (d, J=4.78Hz, 1H), 7.75 (d, J=4.78 Hz, 1H). Exact mass calculated for C₇H₁₀N₂122.08, found 123.1 (MH⁺).

Step B: Preparation of 6-bromo-2,4-dimethylpyridin-3-amine

To a solution of 2,4-dimethylpyridin-3-amine (2.0 g, 16 mmol) in CH₂Cl₂(20 mL), was added a solution of bromine (3.16 g; 20 mmol) in CH₂Cl₂ (5mL) at 0° C. for 5 min. The reaction was concentrated under vacuum. Thereaction was poured into H₂O (50 mL), extracted with CH₂Cl₂, washed withNa₂SO₃ solution, and dried over MgSO₄. The CH₂Cl₂ was concentrated undervacuum to afford the crude compound. The crude was purified over SiO₂ toafford to give 6-bromo-2,4-dimethylpyridin-3-amine. ¹HNMR (CDCl₃, 400MHz) δ 2.10 (s, 3H), 2.31 (s, 3H), 4.85-5.10 (b, 2H), 7.05 (s, 1H).Exact mass calculated for C₇H₉BrN₂ 201.06, found 202.3 (MH⁺).

Step C: Preparation isopropyl4-(6-(6-bromo-2,4-dimethylpyridin-3-ylamino)-5-methoxypyrimidin-4-yloxy)piperidine-1-carboxylate

To a solution of isopropyl4-(6-chloro-5-methoxypyrimidin-4-yloxy)piperidine-1-carboxylate (2.0 g,6.1 mmol) in 10 ml of dioxane, were added6-bromo-2,4-dimethylpyridin-3-amine (1.0 g, 5.1 mmol),2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phospha-bicyclo[3.3.3]undecane(0.35 g, 1.0 mmol), Pd(OAc)₂ (0.11 g, 0.51 mmol), and NaO-t-Bu (1.2 g,12 mmol) at an ambient temperature. The reaction was heated to 150° C.for 3 hrs. The reaction was cooled to room temperature and poured intoH₂O. The organics were extracted with ethyl acetate and dried overMgSO₄. The ethyl acetate was concentrated under vacuum and purified overSiO₂ to give isopropyl4-(6-(6-bromo-2,4-dimethylpyridin-3-ylamino)-5-methoxypyrimidin-4-yloxy)piperidine-1-carboxylate. ¹HNMR (CDCl₃, 400 MHz) δ1.24-1.25 (d, J=6.2 Hz, 6H), 1.72-1.77 (m, 2H), 1.95-2.01 (m, 2H), 2.22(s, 3H), 2.52 (s, 3H), 3.37-3.44 (m, 2H), 3.73-3.79 (m, 2H), 4.91-4.97(m, 1H), 5.30-5.35 (m, 1H), 6.01 (s, 1H), 7.34-7.36 (d, J=8.5 Hz, 1H),8.14-8.16 (d, J=8.5 Hz, 1H), 8.37 (s, 1H). Exact mass calculated forC₂₁H₂₈BrN₅O₄ 494.31, found 495.2 (MH⁺).

Step D: Preparation of isopropyl4-(6-(2,4-dimethyl-6-(methylsulfonyl)pyridin-3-ylamino)-5-methoxypyrimidin-4-yloxy)piperidine-1-carboxylate(Compound 102)

To a solution of isopropyl4-(6-(6-bromo-2,4-dimethylpyridin-3-ylamino)-5-methoxypyrimidin-4-yloxy)piperidine-1-carboxylate(500 mg, 1.0 mmol) in 10 ml of DMSO, were added sodium sulfinate (0.36g, 3.5 mmol), (CuOTf)₂PhH (0.051 g, 0.10 mmol), andN,N′-dimethylethylamine (0.018 g, 0.20 mmol) at an ambient temperature.The reaction was heated to 150° C. for 8 hrs. The reaction was cooled toroom temperature and poured into H₂O. The organics were extracted withethyl acetate and dried over MgSO₄. The ethyl acetate was concentratedunder vacuum and purified over SiO₂ to afford isopropyl4-(6-(2,4-dimethyl-6-(methylsulfonyl)pyridin-3-ylamino)-5-methoxypyrimidin-4-yloxy)piperidine-1-carboxy-late.¹HNMR (CDCl₃, 400 MHz) δ 1.24 (d, J=1.6 Hz, 6H), 1.75-1.81 (m, 2H),1.98-2.02 (m, 2H), 2.25 (s, 3H), 2.65 (s, 3H), 3.21 (s, 3H), 3.52-3.65(m, 2H), 3.65-3.75 (m, 1H), 3.84 (s, 3H), 5.21-5.35 (m, 1H), 7.78 (s,1H), 7.79 (s, 1H), 8.89 (s, 1H). Exact mass calculated for C₂₂H₃₁N₅O₆S493.58, found 494.5 (MH⁺).

Example 9.40 Preparation of4-{6-[6-(1-Methanesulfonyl-1-methyl-ethyl)-2-methyl-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester (Compound 103) Step A: Preparation of6-methyl-5-nitropicolinaldehyde

A solution of 2,6-dimethyl-3-nitropyridine (50 g, 329 mmol) and SeO₂(5.02 g, 27.9 mmol) in dioxane (500 mL) was heated at reflux for 16hours. The solution was filtered, the solvent removed and the residuepurified by column chromatography directly (20% EtOAc/hexanes). Thematerial was recrystalized from ethyl acetate to give 41 g of6-methyl-5-nitropicolinaldehyde (41 g, 75%), a pale yellow solid; ¹HNMR(CDCl₃, 400 MHz) δ 2.94(s, 3H), 7.98 (d, J=8.34, 1H), 8.41 (d, J=8.34,1H), 10.09 (s, 1H). Exact mass calculated for C₇H₆N₂O₃: 166.04, found:167.12 MS m/z (MH⁺).

Step B: Preparation of (6-methyl-5-nitropyridin-2-yl)methanol

A solution of 6-methyl-5-nitropicolinaldehyde (50 g, 329 mmol) inethanol (200 mL) was cooled to 10° C. and sodium borohydride (5.9 g, 157mmol) was added portion-wise. The solution was allowed to stir for onehalf hour, the ethanol was removed and the residue partitioned betweenethyl Acetate and water, the organic phase washed with brine, and driedwith magnesium sulfate and stripped. The residue was purified by columnchromatography (10-40% ethyl acetate/hexanes) to give(6-methyl-5-nitropyridin-2-yl)methanol (12 g, 91%), a pale white solid.¹HNMR (CDCl₃, 400 MHz) δ 2.89(s, 3H), 3.55(t, J=5.05, 1H), 4.83 (d,J=4.55, 2H), 7.31 (d, J=8.34, 1H), 8.31 (d, J=8.34, 1H); Exact masscalculated for C₇H₈N₂O₃:168.05, found: 169.10 MS m/z (MH⁺).

Step C: Preparation of (6-methyl-5-nitropyridin-2-yl)methylmethanesulfonate.

(6-Methyl-5-nitropyridin-2-yl)methanol (12 g, 71 mmol), andtriethylamine (9.4 g, 93 mmol) in THF (300 mL) was chilled in an icebath to 10° C. and methanesulfonyl chloride (9.0 g, 79 mmol) was addeddropwise and the solution was stirred for one hour, then filtered toremove triethylamine HCl, and the solvent was removed under reducedpressure on the rotovap (with the bath temperature at 35° C.) and(6-methyl-5-nitropyridin-2-yl)methyl methanesulfonate (17 g, 97%), abrown oil which was directly used as such. ¹HNMR (CDCl₃, 400 MHz) δ2.87(s, 3H), 3.16(s, 3H), 5.83(s, 2H), 7.55 (d, J=8.34, 1H), 8.38 (d,J=8.34, 1H); Exact mass calculated for C₈H₁₀N₂O₅: 246.03, found: 247.10MS m/z (MH⁺).

Step D: Preparation of 2-methyl-6-(methylsulfonylmethyl)-3-nitropyridine

(6-Methyl-5-nitropyridin-2-yl)methyl methanesulfonate (17.48 g, 71 mmol)was taken up in dmso (100 mL), and NaSO₂Me (25.37 g, 248.5 mmol) wasadded portion wise, the solution heated to 120° C. and stirred for 15minutes, cooled and partitioned between EtOAc and water, the organicphase washed with brine and dried with Magnesium Sulfate and the solventremoved. The residue was washed with 50 mL EtOAc and filtered to yieldthe 2-methyl-6-(methylsulfonyl-methyl)-3-nitropyridine (11.45 g, 70.04%yield), which is of sufficient purity for further use. ¹HNMR (CDCl₃, 400MHz) δ 2.87(s, 3H), 2.99(s, 3H), 4.48(s, 2H), 7.53 (d, J=8.34, 1H), 8.4(d, J=8.34, 1H); Exact mass calculated for C₈H₁₀N₂O₄S: 230.04, found:231.12 MS m/z (MH⁺).

Step E: Preparation of2-methyl-6-(2-(methylsulfonyl)propan-2-yl)-3-nitropyridine.

To a solution of 2-methyl-6-(methylsulfonylmethyl)-3-nitropyridine (1.54g, 6.689 mmol) in 200 mL THF, iodomethane (1.252 mL, 20.07 mmol) andsodium hydride (60% dispersion, 1.1 g, 27.6 mmol) were added. Dark redmixture was stirred at room temperature for 30 minutes and then,quenched with ice-water, partly concentrated, and extracted with CH₂Cl₂and water. Organic phases were dried over MgSO₄, filtered, andconcentrated. Residue was purified by CC(hexane/AcOEt 2:1→1:1) to give2-methyl-6-(2-(methylsulfonyl)propan-2-yl)-3-nitropyridine (1.374 g,80%) as a white solid. ¹HNMR (CDCl₃, 400 MHz) δ 1.92 (s, 6H), 2.85 (s,3H), 2.88 (s, 3H), 7.69-7.71 (d, J=8.6 Hz, 1H), 8.32-8.34 (d, J=8.6 Hz,1H). Exact mass calculated for C₁₀H₁₄N₂O₄S 258.07, found 259.2 (MH⁺).

Step F: Preparation of2-methyl-6-(2-(methylsulfonyl)propan-2-yl)pyridin-3-amine

To a solution of2-methyl-6-(2-(methylsulfonyl)propan-2-yl)-3-nitropyridine (1.27 g, 4.92mmol) in 50 mL acetic acid, zinc dust (1.6 g, 24.5 mmol) was added insmall portions under ice-cooling. After 1 h, more zinc dust (ca. 2 g, 31mmol) was added in small portions and mixture was stirred at roomtemperature for another hour. Solids were filtered off, washed withCH₃CN, and filtrate was concentrated. Residue was purified byCC(CH₂Cl₂/MeOH 20:1+1% NEt₃). Fractions containing product wereconcentrated and re-purified by HPLC. Fractions containing product werepartly concentrated and residue was extracted with 1M NaHCO₃ and CH₂Cl₂.Organic phases were dried over MgSO₄, filtered and concentrated to give2-methyl-6-(2-(methylsulfonyl)propan-2-yl)pyridin-3-amine (0.664 g, 59%yield) as a white solid. ¹HNMR (CDCl₃, 400 MHz) δ 1.84 (s, 6H), 2.39 (s,3H), 2.76 (s, 3H), 3.68 (s, 2H), 6.92-6.94 (d, J=8.3 Hz, 1H), 7.29-7.31(d, J=8.3 Hz, 1H). Exact mass calculated for C₁₀H₁₆N₂O₂S 228.09, found229.2 (MH⁺).

Step G: Preparation of4-{6-[6-(1-Methanesulfonyl-1-methyl-ethyl)-2-methyl-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester (Compound 103)

A mixture of isopropyl4-(6-chloro-5-methoxypyrimidin-4-yloxy)piperidine-1-carboxylate (78.5mg, 0.238 mmol),2-methyl-6-(2-(methylsulfonyl)propan-2-yl)pyridin-3-amine (54.3 mg,0.238 mmol), Pd₂(dba)₃ (20.0 mg, 0.0218 mmol),biphenyl-2-yl-di-tert-butyl-phosphane (3.0 mg, 0.0101 μmol), and cesiumcarbonate (160 mg, 0.491 mmol) in 4M dioxane were heated under microwaveirradiation at 100° C. Mixture was purified by HPLC; fractionscontaining product were partly concentrated, and residue was extractedwith CH₂Cl₂ and 1M NaHCO₃. Organic phases were dried over MgSO₄,filtered, and concentrated to give isopropyl4-(5-methoxy-6-(2-methyl-6-(2-(methylsulfonyl)propan-2-yl)pyridin-3-ylamino)pyrimidin-4-yloxy)piperidine-1-carboxylate(4.6 mg, 4%) as a white solid. ¹HNMR (CDCl₃, 400 MHz) δ 1.16-1.17 (d,J=6.3 Hz, 6H), 1.80-1.86 (m, 2H), 1.87 (s, 6H), 2.01-2.06 (m, 2H), 2.56(s, 3H), 2.81 (s, 3H), 3.38-3.44 (m, 2H), 3.77-3.82 (m, 2H), 3.96 (s,3H), 4.91-4.97 (m, 1H), 5.35-5.39 (m, 1H), 6.98 (s, 1H), 7.51-7.53 (d,J=8.6 Hz, 1H), 8.13 (s, 1H), 8.51-8.53 (d, J=8.6 Hz, 1H). Exact masscalculated for C₂₄H₃₅N₅O₆S 521.23, found 522.5 (MH⁺).

Example 10 Protocol for RUP3 Dose Responses in Melanophores

Melanophores are maintained in culture as reported by Potenza, M. N. andLerner, M. R., in Pigment Cell Research, Vol. 5, 372-378, 1992 andtransfected with the RUP3 expression vector (pCMV) usingelectroporation. Following electroporation, the transfected cells areplated into 96 well plates for the assay. The cells are then allowed togrow for 48 hours in order to both recover from the electroporationprocedure and attain maximal receptor expression levels.

On the assay day, the growth medium on the cells is replaced withserum-free buffer containing 10 nM melatonin. The melatonin acts via anendogenous Gi-coupled GPCR in the melanophores to lower intracellularcAMP levels. In response to lowered cAMP levels, the melanophorestranslocate their pigment to the center of the cell. The net effect ofthis is a significant decrease in the absorbance reading of the cellmonolayer in the well, measured at 600-650 nM.

After a 1-hour incubation in melatonin, the cells become completelypigment-aggregated. At this point a baseline absorbance reading iscollected. Serial dilutions of test compounds are then added to theplate and compounds that stimulate RUP3 produce increases inintracellular cAMP levels. In response to these increased cAMP levels,the melanophores translocate their pigment back into the cell periphery.After one hour, stimulated cells are fully pigment-dispersed. The cellmonolayer in the dispersed state absorbs much more light in the 600-650nm range. The measured increase in absorbance compared to the baselinereading allows one to quantitate the degree of receptor stimulation andplot a dose-response curve.

The compounds in the above examples were screened using the melanophoredispersion assay, as described above. Representative compounds of thepresent invention and their corresponding observed EC₅₀ values are shownin Table 3 below. Certain other compounds illustrated in the Examplesshowed EC₅₀ activities in the melanophore dispersion assay of less thanabout 10 μL. TABLE 3 RUP3 (EC₅₀) Compound (nM) 10 26 24 0.49 76 2.51

Compounds of the present invention have unexpected aqueous solubilities.For example, Compound 77 has an aqueous solubility of 0.19 mg/nL (pH=5)and 1.12 mg/mL (pH=2); and Compound 78 has an aqueous solubility of 0.38mg/mL (pH=5) and 1.45 mg/mL (pH=2).

Each of the embodiments of the present invention may in the alternativebe limited to relate to those compounds that demonstrate about 100 foldor greater binding to RUP3 compared to the corticotrophin-releasingfactor-1 (CRF-1) receptor; a recent review of CRF-1 compounds can befound in Expert Opin. Ther. Patents 2002, 12(11), 1619-1630,incorporated herein by reference in its entirety.

Those skilled in the art will recognize that various modifications,additions, substitutions, and variations to the illustrative examplesset forth herein can be made without departing from the spirit of theinvention and are, therefore, considered within the scope of theinvention. All documents referenced above, including, but not limitedto, printed publications, and provisional and regular patentapplications, are incorporated herein by reference in their entirety.

1. A compound of Formula (Ia):

or a pharmaceutically acceptable salt, solvate or hydrate thereof;wherein: X is N or CR₈ wherein R₈ is H or halogen; Y is NH or O; Z is CHor N; R₁ is carbo-C₁₋₆-alkoxy, oxadiazolyl or pyrimidinyl wherein saidcarbo-C₁₋₆-alkoxy, oxadiazolyl and pyrimidinyl are each optionallysubstituted with 1 or 2 substituents selected independently from thegroup consisting of C₁₋₄ alkyl, C₁₋₄ alkoxy and C₃₋₅ cycloalkyl; R₂ is Hor C₁₋₄ alkyl; R₃ is C₁₋₄ alkoxy, O—C₂₋₄-alkynyl or hydroxyl; R₄ isselected from the group consisting of H, C₁₋₄ alkoxy, C₁₋₄ alkyl, C₂₋₄alkynyl and halogen; R₅ is selected from the group consisting of C₁₋₄acylsulfonamide, C₁₋₄ alkoxy, C₁₋₄ alkyl, C₁₋₄ alkylamino, C₁₋₄alkylsulfonyl, C₁₋₄ alkylthio, cyano, heterocyclyl, di-C₁₋₄-dialkylaminoand sulfonamide, wherein said C₁₋₄ alkoxy, C₁₋₄ alkyl, C₁₋₄ alkylamino,C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, di-C₁₋₄-dialkylamino andheterocyclyl are each optionally substituted with 1 or 2 substituentsselected independently from the group consisting of C₂₋₄ alkynyl, C₁₋₄alkoxy, C₁₋₄ alkylcarboxamide, C₁₋₄ alkylsulfonyl, C₃₋₅ cycloalkyl, C₃₋₅cycloalkyloxy, di-C₁₋₄-alkylcarboxamide, hydroxyl and phosphonooxy,wherein said C₁₋₄ alkylcarboxamide is optionally substituted withhydroxyl; or R₅ is a group of Formula (A):

wherein “m”, “n” and “q” are each independently 0, 1, 2 or 3; “r” is 0,1 or 2; and “t” is 0 or 1; R₆ is H or halogen; and R₇ is H or C₁₋₄alkyl.
 2. The compound according to claim 1 wherein X is N.
 3. Thecompound according to claim 1 wherein X is CR₈.
 4. The compoundaccording to claim 1 wherein R₈ is H or F.
 5. The compound according toclaim 1 wherein Y is NH.
 6. The compound according to claim 1 wherein Yis O.
 7. The compound according to claim 1 wherein Z is CH.
 8. Thecompound according to claim 1 wherein Z is N.
 9. The compound accordingto claim 1 wherein R₁ is carbo-C₁₋₆-alkoxy optionally substituted withC₃₋₅ cycloalkyl.
 10. The compound according to claim 1 wherein R₁ isselected form the group consisting of C(O)OCH₂CH₃, C(O)OCH(CH₃)₂,C(O)OCH(CH₃)(CH₂CH₃), C(O)OCH₂-cyclopropyl, C(O)OCH(CH₃)(cyclopropyl),and C(O)OCH(CH₂CH₃)₂.
 11. The compound according to claim 1 wherein R₁is selected form the group consisting of C(O)OCH₂CH₃, C(O)OCH(CH₃)₂,C(O)OCH(CH₃)(CH₂CH₃), C(O)OCH₂-cyclopropyl andC(O)OCH(CH₃)(cyclopropyl).
 12. The compound according to claim 1 whereinR₁ is oxadiazolyl optionally substituted with one C₁₋₄ alkyl group. 13.The compound according to claim 1 wherein R₁ is5-isopropyl-[1,2,4]oxadiazol-3-yl.
 14. The compound according to claim 1wherein R₁ is pyrimidinyl optionally substituted with one C₁₋₄ alkoxygroup.
 15. The compound according to claim 1 wherein R₁ is5-methoxy-pyrimidin-2-yl.
 16. The compound according to claim 1 whereinR₂ is H.
 17. The compound according to claim 1 wherein R₂ is CH₃. 18.The compound according to claim 1 wherein R₃ is C₁₋₄ alkoxy.
 19. Thecompound according to claim 1 wherein R₃ is OCH₃, OCH₂CH₃, OCH(CH₃)₂,and OCH₂CH₂CH₃.
 20. The compound according to claim 1 wherein R₃ is OCH₃or OCH₂CH₃.
 21. The compound according to claim 1 wherein R₃ is OH orO—C≡CH.
 22. The compound according to claim 1 wherein R₄ is selectedfrom the group consisting of H, OCH₃, CH₃, CH₂CH₃, F, Cl and C≡CH. 23.The compound according to claim 1 wherein R₄ is CH₃.
 24. The compoundaccording to claim 1 wherein R₅ is selected from the group consisting ofOCH₂CH₂CH₃, OCH₂CH₂CH₂OH, S(O)₂CH₃, CH₂CH₂S(O)₂CH₃, NHCH₂CH₂OH, cyano,CH₂CH₂OCH₃, CH₂CH₂OH, CH₂CH₂CH(CH₃)OH, CH₂CH₂OP(O)(OH)₂,S(O)₂NHC(O)CH₂CH₃, CH₂CH₂O-cyclopropyl, NHCH₂CH₂OCH₃, OCH₂CH₂S(O)₂CH₃,NHCH₂CH(CH₃)OH, CH₂CH₂CH₂OH, CH₂CH₂CH₂OP(O)(OH)₂, NHCH₂CH(CH₃)S(O)₂CH₃,N(CH₃)CH₂CH(CH₃)S(O)₂CH₃, 3-methanesulfonyl-pyrrolidin-1-yl,3-methanesulfonyl-piperidin-1-yl, CH₂C(O)N(CH₃)₂,3-methanesulfonyl-azetidin-1-yl, CH₂C(O)NHCH₂CH₂OH, SCH₂CH₂OH,S(O)₂CH₂CH₂OP(O)(OH)₂, S(O)₂CH₂CH₃, NHCH₂CH(OH)CH₂OH, S(O)₂CH₂CH₂OH,OCH₂CH₂OP(O)(OH)₂, OCH₂CH₂CH₂OP(O)(OH)₂, S(O)₂NH₂, CH₃, SCH₂CH₂CH₃,S(O)₂CH₂CH₂CH₃, SCH₂CH₃, SCH(CH₃)₂, S(O)₂CH(CH₃)₂, and CH₂OH.
 25. Thecompound according to claim 1 wherein R₅ is selected from the groupconsisting of OCH₂CH₂CH₃, OCH₂CH₂CH₂OH, S(O)₂CH₃, CH₂CH₂S(O)₂CH₃,NHCH₂CH₂OH, cyano, CH₂CH₂OCH₃, CH₂CH₂OH, CH₂CH₂CH(CH₃)OH,CH₂CH₂OP(O)(OH)₂, S(O)₂NHC(O)CH₂CH₃, CH₂CH₂O-cyclopropyl, NHCH₂CH₂OCH₃,OCH₂CH₂S(O)₂CH₃, NHCH₂CH(CH₃)OH, CH₂CH₂CH₂OH, CH₂CH₂CH₂OP(O)(OH)₂,NHCH₂CH(CH₃)S(O)₂CH₃, N(CH₃)CH₂CH(CH₃)S(O)₂CH₃,3-methanesulfonyl-pyrrolidin-1-yl, 3-methanesulfonyl-piperidin-1-yl,CH₂C(O)N(CH₃)₂, 3-methanesulfonyl-azetidin-1-yl, CH₂C(O)NHCH₂CH₂OH,SCH₂CH₂OH, S(O)₂CH₂CH₂OP(O)(OH)₂, S(O)₂CH₂CH₃, NHCH₂CH(OH)CH₂OH,S(O)₂CH₂CH₂OH, OCH₂CH₂OP(O)(OH)₂, OCH₂CH₂CH₂OP(O)(OH)₂ and S(O)₂NH₂. 26.The compound according to claim 1 wherein R₅ is selected from the groupconsisting of OCH₂CH₂CH₂OH, S(O)₂CH₃, CH₂CH₂S(O)₂CH₃, NHCH₂CH₂OH, cyano,CH₂CH₂OH, CH₂CH₂CH(CH₃)OH, CH₂CH₂OP(O)(OH)₂, S(O)₂NHC(O)CH₂CH₃,CH₂CH₂CH₂OH, S(O)₂CH₂CH₃, NHCH₂CH(OH)CH₂OH, amino, NHCH₂CH₃, NHCH(CH₃)₂and NHCH(CH₃)CH₂CH₃.
 27. The compound according to claim 1 wherein R₅ isa group of Formula (A):

wherein “m”, “n” and “q” are each independently 0, 1, 2 or 3; “r” is 0,1 or 2; and “t” is 0 or
 1. 28. The compound according to claim 1 wherein“m” and “n” are each independently 0 or
 1. 29. The compound according toclaim 1 wherein “q” is 0 or 1 and “r” is 1 or
 2. 30. The compoundaccording to claim 1 wherein R₆ is H.
 31. The compound according toclaim 1 wherein R₆ is F.
 32. The compound according to claim 1 whereinR₇ is H.
 33. The compound according to claim 1 wherein R₇ is CH₃. 34.The compound according to claim 1 having Formula (IIa):

or a pharmaceutically acceptable salt, solvate or hydrate thereof;wherein: Y is NH or O; R₁ is carbo-C₁₋₆-alkoxy optionally substitutedwith C₃₋₅ cycloalkyl; R₂ is H or CH₃; R₃ is C₁₋₄ alkoxy; R₄ is selectedfrom the group consisting of H, OCH₃, CH₃, CH₂CH₃, F and Cl; R₅ isselected from the group consisting of OCH₂CH₂CH₃, OCH₂CH₂CH₂OH,S(O)₂CH₃, CH₂CH₂S(O)₂CH₃, NHCH₂CH₂OH, cyano, CH₂CH₂OCH₃, CH₂CH₂OH,CH₂CH₂CH(CH₃)OH, CH₂CH₂OP(O)(OH)₂, S(O)₂NHC(O)CH₂CH₃,CH₂CH₂O-cyclopropyl, NHCH₂CH₂OCH₃, OCH₂CH₂S(O)₂CH₃, NHCH₂CH(CH₃)OH,CH₂CH₂CH₂OH, CH₂CH₂CH₂OP(O)(OH)₂, NHCH₂CH(CH₃)S(O)₂CH₃,N(CH₃)CH₂CH(CH₃)S(O)₂CH₃, 3-methanesulfonyl-pyrrolidin-1-yl,3-methanesulfonyl-piperidin-1-yl, CH₂C(O)N(CH₃)₂,3-methanesulfonyl-azetidin-1-yl, CH₂C(O)NHCH₂CH₂OH, SCH₂CH₂OH,S(O)₂CH₂CH₂OP(O)(OH)₂, S(O)₂CH₂CH₃, NHCH₂CH(OH)CH₂OH, S(O)₂CH₂CH₂OH,OCH₂CH₂OP(O)(OH)₂, OCH₂CH₂CH₂OP(O)(OH)₂ and S(O)₂NH₂; R₆ is H or F; andR₇ is H or CH₃.
 35. The compound according to claim 1 having Formula(IIc):

or a pharmaceutically acceptable salt, solvate or hydrate thereof;wherein: R₁ is carbo-C₁₋₆-alkoxy optionally substituted with C₃₋₅cycloalkyl; R₂ is H or CH₃; R₃ is C₁₋₄ alkoxy; R₄ is selected from thegroup consisting of H, OCH₃, CH₃, CH₂CH₃, F and Cl; R₅ is selected fromthe group consisting of OCH₂CH₂CH₃, OCH₂CH₂CH₂OH, S(O)₂CH₃,CH₂CH₂S(O)₂CH₃, NHCH₂CH₂OH, cyano, CH₂CH₂OCH₃, CH₂CH₂OH,CH₂CH₂CH(CH₃)OH, CH₂CH₂OP(O)(OH)₂, S(O)₂NHC(O)CH₂CH₃,CH₂CH₂O-cyclopropyl, NHCH₂CH₂OCH₃, OCH₂CH₂S(O)₂CH₃, NHCH₂CH(CH₃)OH,CH₂CH₂CH₂OH, CH₂CH₂CH₂OP(O)(OH)₂, NHCH₂CH(CH₃)S(O)₂CH₃,N(CH₃)CH₂CH(CH₃)S(O)₂CH₃, 3-methanesulfonyl-pyrrolidin-1-yl,3-methanesulfonyl-piperidin-1-yl, CH₂C(O)N(CH₃)₂,3-methanesulfonyl-azetidin-1-yl, CH₂C(O)NHCH₂CH₂OH, SCH₂CH₂OH,S(O)₂CH₂CH₂OP(O)(OH)₂, S(O)₂CH₂CH₃, NHCH₂CH(OH)CH₂OH, S(O)₂CH₂CH₂OH,OCH₂CH₂OP(O)(OH)₂, OCH₂CH₂CH₂OP(O)(OH)₂ and S(O)₂NH₂; R₆ is H or F; andR₇ is H or CH₃.
 36. The compound according to claim 1 having Formula(IIe):

or a pharmaceutically acceptable salt, solvate or hydrate thereof;wherein: R₁ is carbo-C₁₋₆-alkoxy optionally substituted with C₃₋₅cycloalkyl; R₂ is H or CH₃; R₃ is C₁₋₄ alkoxy; R₄ is selected from thegroup consisting of H, OCH₃, CH₃, CH₂CH₃, F and Cl; R₅ is selected fromthe group consisting of OCH₂CH₂CH₃, OCH₂CH₂CH₂OH, S(O)₂CH₃,CH₂CH₂S(O)₂CH₃, NHCH₂CH₂OH, cyano, CH₂CH₂OCH₃, CH₂CH₂OH,CH₂CH₂CH(CH₃)OH, CH₂CH₂OP(O)(OH)₂, S(O)₂NHC(O)CH₂CH₃,CH₂CH₂O-cyclopropyl, NHCH₂CH₂OCH₃, OCH₂CH₂S(O)₂CH₃, NHCH₂CH(CH₃)OH,CH₂CH₂CH₂OH, CH₂CH₂CH₂OP(O)(OH)₂, NHCH₂CH(CH₃)S(O)₂CH₃,N(CH₃)CH₂CH(CH₃)S(O)₂CH₃, 3-methanesulfonyl-pyrrolidin-1-yl,3-methanesulfonyl-piperidin-1-yl, CH₂C(O)N(CH₃)₂,3-methanesulfonyl-azetidin-1-yl, CH₂C(O)NHCH₂CH₂OH, SCH₂CH₂OH,S(O)₂CH₂CH₂OP(O)(OH)₂, S(O)₂CH₂CH₃, NHCH₂CH(OH)CH₂OH, S(O)₂CH₂CH₂OH,OCH₂CH₂OP(O)(OH)₂, OCH₂CH₂CH₂OP(O)(OH)₂ and S(O)₂NH₂; R₆ is H or F; andR₇ is H or CH₃.
 37. The compound according to claim 1 having Formula(IIe):

or a pharmaceutically acceptable salt, solvate or hydrate thereof;wherein: R₁ is carbo-C₁₋₆-alkoxy optionally substituted with C₃₋₅cycloalkyl; R₂ is H or CH₃; R₃ is C₁₋₄ alkoxy; R₄ is selected from thegroup consisting of H, OCH₃, CH₃, CH₂CH₃, F and Cl; R₅ is selected fromthe group consisting of OCH₂CH₂CH₂OH, S(O)₂CH₃, CH₂CH₂S(O)₂CH₃,NHCH₂CH₂OH, cyano, CH₂CH₂OH, CH₂CH₂CH(CH₃)OH, CH₂CH₂OP(O)(OH)₂,S(O)₂NHC(O)CH₂CH₃, CH₂CH₂CH₂OH, S(O)₂CH₂CH₃, NHCH₂CH(OH)CH₂OH andS(O)₂NH₂; R₆ is H or F; and R₇ is H or CH₃.
 38. The compound accordingto claim 1 having Formula (IIg):

or a pharmaceutically acceptable salt, solvate or hydrate thereof;wherein: R₁ is carbo-C₁₋₆-alkoxy optionally substituted with C₃₋₅cycloalkyl; R₂ is H or CH₃; R₃ is C₁₋₄ alkoxy; R₄ is selected from thegroup consisting of H, OCH₃, CH₃, CH₂CH₃, F and Cl; R₅ is selected fromthe group consisting of OCH₂CH₂CH₃, OCH₂CH₂CH₂OH, S(O)₂CH₃,CH₂CH₂S(O)₂CH₃, NHCH₂CH₂OH, cyano, CH₂CH₂OCH₃, CH₂CH₂OH,CH₂CH₂CH(CH₃)OH, CH₂CH₂OP(O)(OH)₂, S(O)₂NHC(O)CH₂CH₃,CH₂CH₂O-cyclopropyl, NHCH₂CH₂OCH₃, OCH₂CH₂S(O)₂CH₃, NHCH₂CH(CH₃)OH,CH₂CH₂CH₂OH, CH₂CH₂CH₂OP(O)(OH)₂, NHCH₂CH(CH₃)S(O)₂CH₃,N(CH₃)CH₂CH(CH₃)S(O)₂CH₃, 3-methanesulfonyl-pyrrolidin-1-yl,3-methanesulfonyl-piperidin-1-yl, CH₂C(O)N(CH₃)₂,3-methanesulfonyl-azetidin-1-yl, CH₂C(O)NHCH₂CH₂OH, SCH₂CH₂OH,S(O)₂CH₂CH₂OP(O)(OH)₂, S(O)₂CH₂CH₃, NHCH₂CH(OH)CH₂OH, S(O)₂CH₂CH₂OH,OCH₂CH₂OP(O)(OH)₂, OCH₂CH₂CH₂OP(O)(OH)₂ and S(O)₂NH₂; R₆ is H or F; andR₇ is H or CH₃.
 39. The compound according to claim 1 having Formula(IIi):

or a pharmaceutically acceptable salt, solvate or hydrate thereof;wherein: “m” and “n” are each independently 0 or 1; “q” is 0 or 1; “r”is 1 or 2; X is N or O; R₁ is carbo-C₁₋₆-alkoxy optionally substitutedwith C₃₋₅ cycloalkyl; R₂ is H or CH₃; R₃ is C₁₋₄ alkoxy; R₄ is selectedfrom the group consisting of H, OCH₃, CH₃, CH₂CH₃, F and Cl; R₆ is H orF; and R₇ is H or CH₃.
 40. The compound according to claim 1 selectedfrom the group consisting of:4-[6-(4-Methanesulfonyl-2-methoxy-phenylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{5-Methoxy-6-[6-(2-methoxy-ethyl)-2-methyl-pyridin-3-ylamino]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[6-(2-Methanesulfonyl-ethyl)-2-methyl-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid 1-cyclopropyl-ethyl ester;4-[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Cyano-2-fluoro-phenylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{6-[6-(2-Hydroxy-ethyl)-2-methyl-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[6-(2-Methanesulfonyl-ethyl)-2-methyl-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{5-Methoxy-6-[6-(2-methoxy-ethylamino)-2-methyl-pyridin-3-ylamino]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[6-(2-Methanesulfonyl-ethoxy)-2-methyl-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[6-(2-Hydroxy-propylamino)-2-methyl-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[6-(3-Hydroxy-propyl)-2-methyl-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{5-Methoxy-6-[2-methyl-6-(3-phosphonooxy-propyl)-pyridin-3-ylamino]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[6-(2-Methanesulfonyl-ethylamino)-2-methoxy-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[6-(2-Methanesulfonyl-propylamino)-2-methyl-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[6-(6-Dimethylcarbamoylmethyl-2-methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-(6-{2-Fluoro-4-[(2-hydroxy-ethylcarbamoyl)-methyl]-phenylamino}-5-methoxy-pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester;4-{6-[6-(2-Methanesulfonyl-ethylamino)-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(2-hydroxy-ethylsulfanyl)-phenylamino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[6-(2,3-Dihydroxy-propylamino)-2-methyl-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[6-(2,3-Dihydroxy-propylamino)-2-methyl-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[6-(2-Hydroxy-ethoxy)-2-methyl-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{5-Methoxy-6-[2-methyl-6-(2-phosphonooxy-ethoxy)-pyridin-3-ylamino]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[6-(3-Hydroxy-propoxy)-2-methyl-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester; and4-{5-Methoxy-6-[2-methyl-6-(3-phosphonooxy-propoxy)-pyridin-3-ylamino]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester; or a pharmaceutically acceptable salt, solvate orhydrate thereof.
 41. The compound according to claim 1 selected from thegroup consisting of:4-[2-(2-Fluoro-4-propoxy-phenylamino)-3-methoxy-pyridin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{2-[2-Fluoro-4-(2-hydroxy-ethyl)-phenylamino]-3-methoxy-pyridin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[5-Fluoro-2-(2-fluoro-4-methanesulfonyl-phenylamino)-3-methoxy-pyridin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{2-[2-Ethyl-4-(2-methanesulfonyl-ethyl)-phenylamino]-3-methoxy-pyridin-4-yloxy}-2-methyl-piperidine-1-carboxylicacid isopropyl ester;4-{5-Fluoro-2-[6-(2-hydroxy-ethoxy)-2-methyl-pyridin-3-ylamino]-3-methoxy-pyridin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{2-[2-Fluoro-4-(2-methanesulfonyl-ethyl)-phenylamino]-3-methoxy-pyridin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{2-[6-(2-Hydroxy-ethylamino)-2-methyl-pyridin-3-ylamino]-3-methoxy-pyridin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[2-(4-Cyano-2-fluoro-phenylamino)-3-methoxy-pyridin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[2-(2-Chloro-4-cyano-phenylamino)-3-methoxy-pyridin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{2-[6-(2-Methanesulfonyl-ethyl)-2-methoxy-pyridin-3-ylamino]-3-methoxy-pyridin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{2-[6-(2-Methanesulfonyl-ethyl)-2-methyl-pyridin-3-ylamino]-3-methoxy-pyridin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{2-[6-(2-Hydroxy-ethyl)-2-methyl-pyridin-3-ylamino]-3-methoxy-pyridin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{2-[6-(3-Hydroxy-butyl)-2-methoxy-pyridin-3-ylamino]-3-methoxy-pyridin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{2-[2-Fluoro-4-(2-hydroxy-ethoxy)-phenylamino]-3-methoxy-pyridin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{3-Ethoxy-2-[2-fluoro-4-(2-phosphonooxy-ethyl)-phenylamino]-pyridin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[3-Methoxy-2-(2-methoxy-4-propionylsulfamoyl-phenylamino)-pyridin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[2-(2,5-Difluoro-4-propoxy-phenylamino)-3-methoxy-pyridin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;(2-Fluoro-4-methanesulfonyl-phenyl)-{4-[1-(5-isopropyl-[1,2,4]oxadiazol-3-yl)-piperidin-4-yloxy]-3-methoxy-pyridin-2-yl}-amine;(2-Fluoro-4-methanesulfonyl-phenyl)-{3-methoxy-4-[1-(5-methoxy-pyrimidin-2-yl)-piperidin-4-yloxy]-pyridin-2-yl}-amine;4-{2-[6-(2-Cyclopropoxy-ethyl)-2-methyl-pyridin-3-ylamino]-3-methoxy-pyridin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[2-(2-Chloro-4-methanesulfonyl-phenylamino)-5-fluoro-3-methoxy-pyridin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[3-Ethoxy-2-(4-methanesulfonyl-2-methoxy-phenylamino)-pyridin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[2-(5-Fluoro-2-methyl-4-propoxy-phenylamino)-3-methoxy-pyridin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{2-[6-(2-Methanesulfonyl-ethyl)-2-methyl-pyridin-3-ylamino]-3-methoxy-pyridin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[2-(2-Fluoro-4-methanesulfonyl-phenylamino)-3-hydroxy-pyridin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[2-(2-Chloro-4-propoxy-phenylamino)-3-methoxy-pyridin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{3-Methoxy-2-[2-methyl-6-(2-phosphonooxy-ethyl)-pyridin-3-ylamino]-pyridin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{2-[6-(2-Methanesulfonyl-ethylamino)-2-methyl-pyridin-3-ylamino]-3-methoxy-pyridin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-(2-{6-[(2-Methanesulfonyl-ethyl)-methyl-amino]-2-methyl-pyridin-3-ylamino}-3-methoxy-pyridin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester;4-{2-[6-(3-Methanesulfonyl-pyrrolidin-1-yl)-2-methyl-pyridin-3-ylamino]-3-methoxy-pyridin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[2-(3-Methanesulfonyl-6′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-ylamino)-3-methoxy-pyridin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{2-[6-(3-Methanesulfonyl-azetidin-1-yl)-2-methyl-pyridin-3-ylamino]-3-methoxy-pyridin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[3-Ethynyloxy-2-(2-fluoro-4-methanesulfonyl-phenylamino)-pyridin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{2-[2-Fluoro-4-(2-phosphonooxy-ethanesulfonyl)-phenylamino]-3-methoxy-pyridin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[2-(4-Ethanesulfonyl-2-fluoro-phenylamino)-3-methoxy-pyridin-4-yloxy]-piperidine-1-carboxylicacid sec-butyl ester;4-{2-[6-(2,3-Dihydroxy-propylamino)-4-methyl-pyridin-3-ylamino]-3-methoxy-pyridin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{2-[6-(2-Hydroxy-ethylsulfanyl)-pyridin-3-ylamino]-3-methoxy-pyridin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{2-[2-Fluoro-4-(2-hydroxy-ethanesulfonyl)-phenylamino]-3-methoxy-pyridin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{2-[6-(2-Hydroxy-ethoxy)-2-methyl-pyridin-3-ylamino]-3-methoxy-pyridin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{3-Methoxy-2-[2-methyl-6-(2-phosphonooxy-ethoxy)-pyridin-3-ylamino]-pyridin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{2-[6-(3-Hydroxy-propoxy)-2-methyl-pyridin-3-ylamino]-3-methoxy-pyridin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{3-Methoxy-2-[2-methyl-6-(3-phosphonooxy-propoxy)-pyridin-3-ylamino]-pyridin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[3-Methoxy-2-(2-methoxy-4-sulfamoyl-phenylamino)-pyridin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{2-[2-Fluoro-4-(3-phosphonooxy-propyl)-phenylamino]-3-methoxy-pyridin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{2-[6-(2-Hydroxy-ethyl)-2-methyl-pyridin-3-ylamino]-3-methoxy-pyridin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{3-Methoxy-2-[2-methyl-6-(2-phosphonooxy-ethyl)-pyridin-3-ylamino]-pyridin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{2-[6-(3-Hydroxy-propyl)-2-methyl-pyridin-3-ylamino]-3-methoxy-pyridin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester; and4-{3-Methoxy-2-[2-methyl-6-(3-phosphonooxy-propyl)-pyridin-3-ylamino]-pyridin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester; or a pharmaceutically acceptable salt, solvate orhydrate thereof.
 42. The compound according to claim 1 selected from thegroup consisting of:4-[6-(2,6-Dimethyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(6-Methanesulfonyl-2-methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(6-Methanesulfonyl-4-methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[5-Methoxy-6-(2-methyl-6-propylsulfanyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{5-Methoxy-6-[2-methyl-6-(propane-1-sulfonyl)-pyridin-3-ylamino]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[6-(6-Ethylsulfanyl-2-methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(6-Ethanesulfonyl-2-methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(6-Isopropylsulfanyl-2-methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{5-Methoxy-6-[2-methyl-6-(propane-2-sulfonyl)-pyridin-3-ylamino]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[6-(2-Hydroxy-ethanesulfonyl)-2-methyl-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[5-Hydroxy-6-(6-methanesulfonyl-2-methyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[5-Ethoxy-6-(6-methanesulfonyl-2-methyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[5-Isopropoxy-6-(6-methanesulfonyl-2-methyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(6-Methanesulfonyl-2-methyl-pyridin-3-ylamino)-5-propoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(6-Methanesulfonyl-2-methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid 1-ethyl-propyl ester;4-[6-(6-Methanesulfonyl-2-methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid sec-butyl ester;4-[6-(6-Cyano-4-methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester; and4-[6-(6-Hydroxymethyl-4-methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;{6-[1-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-5-methoxy-pyrimidin-4-yl}-(6-methanesulfonyl-2-methyl-pyridin-3-yl)-amine;4-[6-(6-Methanesulfonyl-2,4-dimethyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester; and4-{6-[6-(1-Methanesulfonyl-1-methyl-ethyl)-2-methyl-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl; or a pharmaceutically acceptable salt, solvate orhydrate thereof.
 43. A pharmaceutical composition comprising at leastone compound according to claim 1, 40, 41, or 42, and a pharmaceuticallyacceptable carrier.
 44. A method for treatment of a metabolic-relateddisorder in an individual comprising administering to said individual inneed of such treatment a therapeutically effective amount of a compoundaccording to claim 1, 40, 41, or
 42. 45. The method according to claim44 wherein said metabolic-related disorder is selected from the groupconsisting of type I diabetes, type II diabetes, inadequate glucosetolerance, insulin resistance, hyperglycemia, hyperlipidemia,hypertriglyceridemia, hypercholesterolemia, dyslipidemia and syndrome X.46. The method according to claim 44 wherein said metabolic-relateddisorder is type II diabetes.
 47. A method of decreasing food intake ofan individual comprising administering to said individual in needthereof a therapeutically effective amount of a compound according toclaim
 1. 48. A method of inducing satiety in an individual comprisingadministering to said individual in need thereof a therapeuticallyeffective amount of a compound according to claim
 1. 49. A method ofcontrolling or decreasing weight gain of an individual comprisingadministering to said individual in need thereof a therapeuticallyeffective amount of a compound according to claim
 1. 50. A method ofmodulating a RUP3 receptor in an individual comprising contacting thereceptor with a compound according to claim 1, 40, 41, or
 42. 51. Themethod of modulating the RUP3 receptor according to claim 50 whereinsaid compound is an agonist.
 52. The method of modulating the RUP3receptor according to claim 50 wherein said modulation of the RUP3receptor is for treatment of a metabolic-related disorder.
 53. Themethod of modulating the RUP3 receptor according to claim 52 whereinsaid metabolic-related disorder is selected from the group consisting oftype I diabetes, type II diabetes, inadequate glucose tolerance, insulinresistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia,hypercholesterolemia, dyslipidemia and syndrome X.
 54. The method ofmodulating the RUP3 receptor according to claim 52 wherein saidmetabolic-related disorder is type II diabetes.
 55. The method ofmodulating the RUP3 receptor according to claim 50 wherein saidmodulation of the RUP3 receptor reduces food intake of said individual.56. The method of modulating the RUP3 receptor according to claim 50wherein said modulation of the RUP3 receptor induces satiety in saidindividual.
 57. The method of modulating the RUP3 receptor according toclaim 50 wherein said modulation of the RUP3 receptor controls orreduces weight gain of said individual.
 58. A method of producing apharmaceutical composition comprising admixing a compound of claim 1,40, 41, or 42 and a pharmaceutically acceptable carrier.